Methods for reducing cellular proliferation and treating certain diseases

ABSTRACT

Disclosed herein are methods of treating cancer and/or reducing cellular proliferation in a patient, comprising identifying a patient in need of treatment and administering a therapeutically effective amount of at least one cationic steroid antimicrobial (CSA), or a pharmaceutically acceptable salt thereof. Kits comprising such compositions and instructions on such methods are also contemplated herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/149,675, filed Jan. 7, 2014, which claims benefit of U.S. ProvisionalApplication No. 61/749,800, filed Jan. 7, 2013, the disclosures of whichare incorporated herein by reference in their entirety.

BACKGROUND Field

Cationic steroid antimicrobials (“CSAs”) for treating certain diseasessuch as cancer and/or reducing cellular proliferation.

Description of the Related Art

Cancer is a term used for diseases in which abnormal cells dividewithout control and may invade other tissues. Cancer cells may alsospread to other parts of the body through the blood and lymph systems.

There are more than 100 different types of cancer, with most cancersnamed for the organ or type of cell in which they start. For example,cancer that begins in the colon may be referred to as colon cancer;cancer that begins in basal cells of the skin may be referred to asbasal cell carcinoma. Common types of cancer in the United States areBladder Cancer, Lung Cancer, Breast Cancer, Melanoma, Colon and RectalCancer, Non-Hodgkin Lymphoma, Endometrial Cancer, Pancreatic Cancer,Kidney (Renal Cell) Cancer, Prostate Cancer, Leukemia, and thyroidCancer.

Cancer types can also be grouped into broader categories. The maincategories of cancer include: carcinoma—cancer that begins in the skinor in tissues that line or cover internal organs; sarcoma—cancer thatbegins in bone, cartilage, fat, muscle, blood vessels, or otherconnective or supportive tissue; leukemia—cancer that starts inblood-forming tissue such as the bone marrow and causes large numbers ofabnormal blood cells to be produced and enter the blood; lymphoma andmyeloma—cancers that begin in the cells of the immune system; centralnervous system cancers—cancers that begin in the tissues of the brainand spinal cord.

Several techniques for treating cancer are known in the art. Suchtechniques include chemotherapy, radiation therapy, surgery, andtransplantation. Each of these techniques, however, have undesirableside effects and varying success rates. Indeed, U.S. statistics for 2012indicate that there will be an estimated 1,638,910 new cases of cancer(not including non-melanoma skin cancers) and 577,190 estimated deathsfrom cancer. Therefore, a need exists to develop new methods fortreating cancer and/or diseases associated with cellular proliferation.

SUMMARY

Disclosed herein are methods of treating cancer and/or reducing cellularproliferation in a patient, comprising identifying a patient in need oftreatment and administering a therapeutically effective amount of atleast one cationic steroid antimicrobial (CSA), or a pharmaceuticallyacceptable salt thereof. We have discovered that CSAs haveanti-proliferative activity against a wide variety of cell lines,including known cancerous cell lines, and have demonstrated bothanti-proliferative and cytotoxic activities. Kits comprising suchcompositions and instructions on such methods are also contemplatedherein.

In some embodiments, the cancer is leukemia, non-small cell lung cancer,colon cancer, CNS cancer, skin cancer, ovarian cancer, renal cancer,prostate cancer, breast cancer, or multiple myeloma. In someembodiments, the cancer is leukemia, non-small cell lung cancer, coloncancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostatecancer, or breast cancer.

In other embodiments, the method reduces the proliferation of cellsand/or cell lines by contacting a CSA with a cell and/or cell line suchas CCRF-CEM; HL-60(TB); K-562; MOLT-4; RPMI-8226; SR; A549/ATCC; EKVX;HOP-62; HOP-92; NCI-H226; NCI-H23; NCI-H322M; NCI-H460; NCI-H522; COLO205; HCC-2998; HCT-116; HCT-15; HT29; KM12; SW-620; SF-268; SF-295;SF-539; SNB-19; SNB-75; U251; LOX IMVI; MALME-3M; M14; SK-MEL-2;SK-MEL-28; SK-MEL-5; UACC-257; UACC-62; IGROV1; OVCAR-3; OVCAR-4;OVCAR-5; OVCAR-8; NCI/ADR-RES; SK-OV-3; 786-0; A4981; ACHN; CAKI-1; RXF393; SN12C; TK-10; UO-31; PC-3; DU-145; MCF7; NCI-ADR-RES;MDA-MB-231/ATCC; HS 578T; MDA-MB-435; MDA-MB-468; BT-549; or T-47D. Anembodiment also includes contacting cells of a patient with a CSAwherein the cells are cancer cells of the type represented by theforegoing cell lines.

In some embodiments, the CSA is a compound of Formula (I) or apharmaceutically acceptable salt thereof:

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is selected from the compound of Formula (II):

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is selected from the compound of Formula (III):

In some embodiments rings A, B, C, and D are independently saturated, orare fully or partially unsaturated, provided that at least two of ringsA, B, C, and D are saturated; m, n, p, and q are independently 0 or 1;R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ are independentlyselected from the group consisting of hydrogen, hydroxyl, a substitutedor unsubstituted alkyl, a substituted or unsubstituted hydroxyalkyl, asubstituted or unsubstituted alkyloxyalkyl, a substituted orunsubstituted alkylcarboxyalkyl, a substituted or unsubstitutedalkylaminoalkyl, a substituted or unsubstituted alkylaminoalkylamino, asubstituted or unsubstituted alkylaminoalkylaminoalkylamino, asubstituted or unsubstituted aminoalkyl, a substituted or unsubstitutedaryl, a substituted or unsubstituted arylaminoalkyl, a substituted orunsubstituted haloalkyl, a substituted or unsubstituted alkenyl, asubstituted or unsubstituted alkynyl, oxo, a linking group attached to asecond steroid, a substituted or unsubstituted aminoalkyloxy, asubstituted or unsubstituted aminoalkyloxyalkyl, a substituted orunsubstituted aminoalkylcarboxy, a substituted or unsubstitutedaminoalkylaminocarbonyl, a substituted or unsubstitutedaminoalkylcarboxamido, a substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, asubstituted or unsubstituted azidoalkyloxy, a substituted orunsubstituted cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, a substituted orunsubstituted guanidinoalkyloxy, a substituted or unsubstitutedquaternary ammonium alkylcarboxy, and a substituted or unsubstitutedguanidinoalkyl carboxy, where Q₅ is a side chain of any amino acid(including a side chain of glycine, i.e., H), and P.G. is an aminoprotecting group; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, a substituted or unsubstituted alkyl,a substituted or unsubstituted hydroxyalkyl, a substituted orunsubstituted alkyloxyalkyl, a substituted or unsubstituted aminoalkyl,a substituted or unsubstituted aryl, a substituted or unsubstitutedhaloalkyl, a substituted or unsubstituted alkenyl, a substituted orunsubstituted alkynyl, oxo, a linking group attached to a secondsteroid, a substituted or unsubstituted aminoalkyloxy, a substituted orunsubstituted aminoalkylcarboxy, a substituted or unsubstitutedaminoalkylaminocarbonyl, a substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,azidoalkyloxy, cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, guanidinoalkyloxy,and guanidinoalkylcarboxy, where Q₅ is a side chain of any amino acid,P.G. is an amino protecting group, provided that at least two or threeof R₁₋₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ are independentlyselected from the group consisting of a substituted or unsubstitutedaminoalkyl, a substituted or unsubstituted aminoalkyloxy, a substitutedor unsubstituted alkylcarboxyalkyl, a substituted or unsubstitutedalkylaminoalkylamino, a substituted or unsubstitutedalkylaminoalkylaminoalkylamino, a substituted or unsubstitutedaminoalkylcarboxy, a substituted or unsubstituted arylaminoalkyl, asubstituted or unsubstituted aminoalkyloxyaminoalkylaminocarbonyl, asubstituted or unsubstituted aminoalkylaminocarbonyl, a substituted orunsubstituted aminoalkylcarboxyamido, a quaternary ammoniumalkylcarboxy, a substituted or unsubstituted di(alkyl)aminoalkyl,H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstitutedguanidinoalkyloxy, and a substituted or unsubstitutedguanidinoalkylcarboxy.

In some embodiments, R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈are independently selected from the group consisting of hydrogen,hydroxyl, a substituted or unsubstituted (C₁-C₁₈) alkyl, a substitutedor unsubstituted (C₁-C₁₈) hydroxyalkyl, a substituted or unsubstituted(C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, a substituted or unsubstituted(C₁-C₁₈) alkylcarboxy-(C₁-C₁₈) alkyl, a substituted or unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, a substituted or unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, a substituted or unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, asubstituted or unsubstituted (C₁-C₁₈) aminoalkyl, a substituted orunsubstituted aryl, a substituted or unsubstituted arylamino-(C₁-C₁₈)alkyl, a substituted or unsubstituted (C₁-C₁₈) haloalkyl, a substitutedor unsubstituted C₂-C₆ alkenyl, a substituted or unsubstituted C₂-C₆alkynyl, oxo, a linking group attached to a second steroid, asubstituted or unsubstituted (C₁-C₁₈) aminoalkyloxy, a substituted orunsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, a substituted orunsubstituted (C₁-C₁₈) aminoalkylcarboxy, a substituted or unsubstituted(C₁-C₁₈) aminoalkylaminocarbonyl, a substituted or unsubstituted(C₁-C₁₈) aminoalkylcarboxamido, a substituted or unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, asubstituted or unsubstituted (C₁-C₁₈) azidoalkyloxy, a substituted orunsubstituted (C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, asubstituted or unsubstituted (C₁-C₁₈) guanidinoalkyloxy, a substitutedor unsubstituted (C₁-C₁₈) quaternary ammonium alkylcarboxy, and asubstituted or unsubstituted (C₁-C₁₈) guanidinoalkyl carboxy, where Q₅is a side chain of any amino acid (including a side chain of glycine,i.e., H), and P.G. is an amino protecting group; R₅, R₈, R₉, R₁₀, R₁₃,R₁₄ and R₁₇ are independently deleted when one of rings A, B, C, or D isunsaturated so as to complete the valency of the carbon atom at thatsite, or R₅, R₈, R₉, R₁₀, R₁₃, and R₁₄ are independently selected fromthe group consisting of hydrogen, hydroxyl, a substituted orunsubstituted (C₁-C₁₈) alkyl, a substituted or unsubstituted (C₁-C₁₈)hydroxyalkyl, a substituted or unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈)alkyl, a substituted or unsubstituted (C₁-C₁₈) aminoalkyl, a substitutedor unsubstituted aryl, a substituted or unsubstituted (C₁-C₁₈)haloalkyl, a substituted or unsubstituted (C₂-C₆) alkenyl, a substitutedor unsubstituted (C₂-C₆) alkynyl, oxo, a linking group attached to asecond steroid, a substituted or unsubstituted (C₁-C₁₈) aminoalkyloxy, asubstituted or unsubstituted (C₁-C₁₈) aminoalkylcarboxy, a substitutedor unsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, a substituted orunsubstituted di(C₁-C₁₈ alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, a substituted or unsubstituted (C₁-C₁₈)azidoalkyloxy, a substituted or unsubstituted (C₁-C₁₈) cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, a substituted or unsubstituted (C₁-C₁₈)guanidinoalkyloxy, and (C₁-C₁₈) guanidinoalkylcarboxy, where Q5 is aside chain of any amino acid, and P.G. is an amino protecting group;provided that at least two or three of R₁₋₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆,R₁₇, and R₁₈ are independently selected from the group consisting of asubstituted or unsubstituted (C₁-C₈) aminoalkyl, a substituted orunsubstituted (C₁-C₈) aminoalkyloxy, a substituted or unsubstituted(C₁-C₈) alkylcarboxy-(C₁-C₁₈) alkyl, a substituted or unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, a substituted or unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₈) alkylamino (C₁-C₈) alkylamino, a substitutedor unsubstituted (C₁-C₁₈) aminoalkylcarboxy, a substituted orunsubstituted arylamino (C₁-C₈) alkyl, a substituted or unsubstituted(C₁-C₈) aminoalkyloxy (C₁-C₁₈) aminoalkylaminocarbonyl, a substituted orunsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, a substituted orunsubstituted (C₁-C₁₈) aminoalkylcarboxyamido, a substituted orunsubstituted (C₁-C₈) quaternary ammonium alkylcarboxy, a substituted orunsubstituted di(C₁-C₁₈ alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, a substituted or unsubstituted (C₁-C₁₈)azidoalkyloxy, a substituted or unsubstituted (C₁-C₁₈) cyanoalkyloxy,P.G.-HN—HC(Q5)-C(O)—O—, a substituted or unsubstituted (C₁-C₁₈)guanidinoalkyloxy, and a substituted or unsubstituted (C₁-C₁₈)guanidinoalkylcarboxy.

In some embodiments, R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈are independently selected from the group consisting of hydrogen,hydroxyl, an unsubstituted (C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)hydroxyalkyl, unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈) alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted (C₁-C₁₈) aminoalkyl, anunsubstituted aryl, an unsubstituted arylamino-(C₁-C₁₈) alkyl, oxo, anunsubstituted (C₁-C₁₈) aminoalkyloxy, an unsubstituted (C₁-C₁₈)aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxy, an unsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, anunsubstituted (C₁-C₁₈) aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, unsubstituted (C₁-C₁₈) guanidinoalkyloxy,unsubstituted (C₁-C₁₈) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-C₁₈) guanidinoalkyl carboxy; R₅, R₈, R₉, R₁₀, R₁₃, R₁₄and R₁₇ are independently deleted when one of rings A, B, C, or D isunsaturated so as to complete the valency of the carbon atom at thatsite, or R₅, R₈, R₉, R₁₀, R₁₃, and R₁₄ are independently selected fromthe group consisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; provided that at least two or three of R₁₋₄, R₆,R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from thegroup consisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-Cis)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-Cis)guanidinoalkyl carboxy.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of hydrogen, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted arylamino-(C₁-C₁₈) alkyl, anunsubstituted (C₁-C₁₈) aminoalkyloxy, an unsubstituted (C₁-C₁₈)aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxy, an unsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, anunsubstituted (C₁-C₁₈) aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, unsubstituted (C₁-C₁₈) guanidinoalkyloxy,unsubstituted (C₁-C₁₈) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-Cis) guanidinoalkyl carboxy; and R₁, R₂, R₄, R₅, R₆,R₈, R₉, R₁₀, R₁₁, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently selectedfrom the group consisting of hydrogen and unsubstituted (C₁-C₆) alkyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of hydrogen, an unsubstituted (C₁-C₆) alkyl,unsubstituted (C₁-C₆) hydroxyalkyl, unsubstituted (C₁-C₁₆)alkyloxy-(C₁-C₅) alkyl, unsubstituted (C₁-C₁₆) alkylcarboxy-(C₁-C₅)alkyl, unsubstituted (C₁-C₁₆) alkylamino-(C₁-C₅)alkyl, (C₁-C₁₆)alkylamino-(C₁-C₅) alkylamino, unsubstituted (C₁-C₁₆)alkylamino-(C₁-C₁₆) alkylamino-(C₁-C₅) alkylamino, an unsubstituted(C₁-C₁₆) aminoalkyl, an unsubstituted arylamino-(C₁-C₅) alkyl, anunsubstituted (C₁-C₅) aminoalkyloxy, an unsubstituted (C₁-C₁₆)aminoalkyloxy-(C₁-C₅) alkyl, an unsubstituted (C₁-C₅) aminoalkylcarboxy,an unsubstituted (C₁-C₅) aminoalkylaminocarbonyl, an unsubstituted(C₁-C₅) aminoalkylcarboxamido, an unsubstituted di(C₁-C₅alkyl)amino-(C₁-C₅) alkyl, unsubstituted (C₁-C₅) guanidinoalkyloxy,unsubstituted (C₁-C₁₆) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-C₁₆) guanidinoalkylcarboxy;

In some embodiments, R₁, R₂, R₄, R₅, R₆, R₈, R₁₀, R₁₁, R₁₄, R₁₆, and R₁₇are each hydrogen; and R₉ and R₁₃ are each methyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of aminoalkyloxy; aminoalkylcarboxy;alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl;di(alkyl)aminoalkyl; alkoxycarbonylalkyl; and alkylcarboxyalkyl.

In some embodiments, R₃, R₇, and R₁₂ are independently selected from thegroup consisting of aminoalkyloxy and aminoalkylcarboxy; and R₁₈ isselected from the group consisting of alkylaminoalkyl;alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl;alkylaminoalkyl; alkyoxycarbonylalkyl; and alkylcarboxyalkyl.

In some embodiments, R₃, R₇, and R₁₂ are the same. In some embodiments,R₃, R₇, and R₁₂ are aminoalkyloxy. In some embodiments, R₃, R₇, and R₁₂are aminoalkylcarboxy.

In some embodiments, R18 is alkylaminoalkyl. In some embodiments,alkoxycarbonylalkyl. In some embodiments, R₁₈ is di(alkyl)aminoalkyl. Insome embodiments, R₁₈ is alkylcarboxyalkyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of amino-C₃-alkyloxy; amino-C₃-alkyl-carboxy;C₈-alkylamino-C₅-alkyl; C₈-alkoxy-carbonyl-C₄-alkyl;C₈-alkyl-carbonyl-C₄-alkyl; di-(C₅-alkyl)amino-C₅-alkyl;C₁₃-alkylamino-C₅-alkyl; C₆-alkoxy-carbonyl-C₄-alkyl;C₆-alkyl-carboxy-C₄-alkyl; and C₁₆-alkylamino-C₅-alkyl.

In some embodiments, m, n, and p are each 1 and q is 0.

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is:

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In some embodiments, the pharmaceutically acceptable salt is ahydrochloride salt. In some embodiments, the pharmaceutically acceptablesalt is a mono-hydrochloride salt, a di-hydrochloride salt, atri-hydrochloride salt, or a tetra-hydrochloride salt.

In some embodiments, the method further comprises administering anon-CSA chemotherapeutic agent to the patient. Such non-CSAchemotherapeutic agents include alkylating agents, anthracyclines,cytoskeletal disruptors, epothilones, histone deacetylase inhibitors,topoisomerase inhibitors, kinase inhibitors, monoclonal antibodies,nucleotide analogs, peptide antibiotics, platinum-based agents,retinoids, and vinca alkaloids.

In some embodiments, the method further comprises administering acompound to alleviate nausea and/or pain.

In some embodiments, the CSA is not

Some embodiments are directed to a compound having the followingstructure, or a pharmaceutically acceptable salt thereof:

In some embodiments, the pharmaceutically acceptable salt is ahydrochloride salt, or specifically a tetra-hydrochloride salt.

Some embodiments are directed to the use of companion diagnostics toidentify an appropriate treatment for the patient. In some embodiments,the CSA is selected by measuring a biomarker in the patient. Thebiomarker can be a cellular response to the CSA, such as cytotoxicity.In some embodiments, one or more chemotherapeutic agents are selected bysubjecting a sample from the patient to a companion diagnostic device.

Some embodiments are directed to a CSA complexed with albumin and/or asurfactant. Other embodiments are directed to a pharmaceuticalcomposition comprising CSA and albumin. Some embodiments are directed toa pharmaceutical composition comprising CSA and miranol.

Additional features and advantages will be set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the embodiments disclosedherein. The objects and advantages of the embodiments disclosed hereinwill be realized and attained by means of the elements and combinationsparticularly pointed out in the appended claims. It is to be understoodthat both the foregoing brief summary and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the embodiments disclosed herein or as claimed.

DETAILED DESCRIPTION

The embodiments disclosed herein will now be described by reference tosome more detailed embodiments, with occasional reference to theaccompanying drawings. These embodiments may, however, be embodied indifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the embodiments to those skilled in the art.

Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which these embodiments belong. The terminology used in thedescription herein is for describing particular embodiments only and isnot intended to be limiting of the embodiments. As used in thespecification and the appended claims, the singular forms “a,” “an,” and“the” are intended to include the plural forms as well, unless thecontext clearly indicates otherwise. All publications, patentapplications, patents, and other references mentioned herein areincorporated by reference in their entirety.

Terms and phrases used in this application, and variations thereof,especially in the appended claims, unless otherwise expressly stated,should be construed as open ended as opposed to limiting. As examples ofthe foregoing, the term ‘including’ should be read to mean ‘including,without limitation,’ ‘including but not limited to,’ or the like; theterm ‘comprising’ as used herein is synonymous with ‘including,’‘containing,’ or ‘characterized by,’ and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps; theterm ‘having’ should be interpreted as ‘having at least;’ the term‘includes’ should be interpreted as ‘includes but is not limited to;’the term ‘example’ is used to provide exemplary instances of the item indiscussion, not an exhaustive or limiting list thereof, and use of termslike ‘preferably,’ ‘preferred,’ ‘desired,’ or ‘desirable,’ and words ofsimilar meaning should not be understood as implying that certainfeatures are critical, essential, or even important to the structure orfunction of the invention, but instead as merely intended to highlightalternative or additional features that may or may not be utilized in aparticular embodiment. In addition, the term “comprising” is to beinterpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of acompound, composition or device, the term “comprising” means that thecompound, composition or device includes at least the recited featuresor components, but may also include additional features or components.Likewise, a group of items linked with the conjunction ‘and’ should notbe read as requiring that each and every one of those items be presentin the grouping, but rather should be read as ‘and/or’ unless expresslystated otherwise. Similarly, a group of items linked with theconjunction ‘or’ should not be read as requiring mutual exclusivityamong that group, but rather should be read as ‘and/or’ unless expresslystated otherwise.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, racemicmixture, diastereomerically pure, diastereomerically enriched, or astereoisomeric mixture. In addition it is understood that, in anycompound described herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z a mixture thereof.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

It is to be understood that where compounds disclosed herein haveunfilled valencies, then the valencies are to be filled with hydrogensor isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2(deuterium).

It is understood that the compounds described herein can be labeledisotopically. Substitution with isotopes such as deuterium may affordcertain therapeutic advantages resulting from greater metabolicstability, such as, for example, increased in vivo half-life or reduceddosage requirements. Each chemical element as represented in a compoundstructure may include any isotope of said element. For example, in acompound structure a hydrogen atom may be explicitly disclosed orunderstood to be present in the compound. At any position of thecompound that a hydrogen atom may be present, the hydrogen atom can beany isotope of hydrogen, including but not limited to hydrogen-1(protium) and hydrogen-2 (deuterium). Thus, reference herein to acompound encompasses all potential isotopic forms unless the contextclearly dictates otherwise.

It is understood that the methods and combinations described hereininclude crystalline forms (also known as polymorphs, which include thedifferent crystal packing arrangements of the same elemental compositionof a compound), amorphous phases, salts, solvates, and hydrates. In someembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, or thelike. In other embodiments, the compounds described herein exist inunsolvated form. Solvates contain either stoichiometric ornon-stoichiometric amounts of a solvent, and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water, ethanol, or the like. Hydrates are formed when thesolvent is water, or alcoholates are formed when the solvent is alcohol.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present embodiments. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldbe construed in light of the number of significant digits and ordinaryrounding approaches.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the embodiments are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Every numerical range given throughoutthis specification and claims will include every narrower numericalrange that falls within such broader numerical range, as if suchnarrower numerical ranges were all expressly written herein. Where arange of values is provided, it is understood that the upper and lowerlimit, and each intervening value between the upper and lower limit ofthe range is encompassed within the embodiments.

As used herein, any “R” group(s) such as, without limitation, R₁, R₂,R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, andR₁₈ represent substituents that can be attached to the indicated atom.Unless otherwise specified, an R group may be substituted orunsubstituted.

A “ring” as used herein can be heterocyclic or carbocyclic. The term“saturated” used herein refers to a ring having each atom in the ringeither hydrogenated or substituted such that the valency of each atom isfilled. The term “unsaturated” used herein refers to a ring where thevalency of each atom of the ring may not be filled with hydrogen orother substituents. For example, adjacent carbon atoms in the fused ringcan be doubly bound to each other. Unsaturation can also includedeleting at least one of the following pairs and completing the valencyof the ring carbon atoms at these deleted positions with a double bond;such as R₅ and R₉ R₈ and R₁₀; and R₁₃ and R₁₄.

Whenever a group is described as being “substituted” that group may besubstituted with one, two, three or more of the indicated substituents,which may be the same or different, each replacing a hydrogen atom. Ifno substituents are indicated, it is meant that the indicated“substituted” group may be substituted with one or more group(s)individually and independently selected from alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, acylalkyl, alkoxyalkyl,aminoalkyl, amino acid, aryl, heteroaryl, heteroalicyclyl, aralkyl,heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl,alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen(e.g., F, Cl, Br, and I), thiocarbonyl, O-carbamyl, N-carbamyl,O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato,thiocyanato, isothiocyanato, nitro, oxo, silyl, sulfenyl, sulfinyl,sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl,trihalomethanesulfonamido, an amino, a mono-substituted amino group anda di-substituted amino group, R^(a)O(CH₂)_(m)O—, R^(b)(CH₂)_(n)O—,R^(c)C(O)O(CH₂)_(p)O—, and protected derivatives thereof. Thesubstituent may be attached to the group at more than one attachmentpoint. For example, an aryl group may be substituted with a heteroarylgroup at two attachment points to form a fused multicyclic aromatic ringsystem. Biphenyl and naphthalene are two examples of an aryl group thatis substituted with a second aryl group.

As used herein, “C_(a)” or “C_(a) to C_(b)” in which “a” and “b” areintegers refer to the number of carbon atoms in an alkyl, alkenyl oralkynyl group, or the number of carbon atoms in the ring of acycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl orheteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of thecycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring ofthe aryl, ring of the heteroaryl or ring of the heteroalicyclyl cancontain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a“C₁ to C₄ alkyl” group refers to all alkyl groups having from 1 to 4carbons, that is, CH₃—, CH₃CH₂—, CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—,CH₃CH₂CH(CH₃)— and (CH₃)₃C—. If no “a” and “b” are designated withregard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl,cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadestrange described in these definitions is to be assumed.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 25 carbon atoms(whenever it appears herein, a numerical range such as “1 to 25” refersto each integer in the given range; e.g., “1 to 25 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 25 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 15 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₄” or “C₁-C₄ alkyl” or similar designations. Byway of example only, “C₁-C₄ alkyl” indicates that there are one to fourcarbon atoms in the alkyl chain, i.e., the alkyl chain is selected frommethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, andt-butyl. Typical alkyl groups include, but are in no way limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl,pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

As used herein, “alkenyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more double bonds. Thealkenyl group may have 2 to 25 carbon atoms (whenever it appears herein,a numerical range such as “2 to 25” refers to each integer in the givenrange; e.g., “2 to 25 carbon atoms” means that the alkenyl group mayconsist of 2 carbon atom, 3 carbon atoms, 4 carbon atoms, etc., up toand including 25 carbon atoms, although the present definition alsocovers the occurrence of the term “alkenyl” where no numerical range isdesignated). The alkenyl group may also be a medium size alkenyl having2 to 15 carbon atoms. The alkenyl group could also be a lower alkenylhaving 1 to 6 carbon atoms. The alkenyl group of the compounds may bedesignated as “C₄” or “C₂-C₄ alkyl” or similar designations. An alkenylgroup may be unsubstituted or substituted.

As used herein, “alkynyl” refers to an alkyl group that contains in thestraight or branched hydrocarbon chain one or more triple bonds. Thealkynyl group may have 2 to 25 carbon atoms (whenever it appears herein,a numerical range such as “2 to 25” refers to each integer in the givenrange; e.g., “2 to 25 carbon atoms” means that the alkynyl group mayconsist of 2 carbon atom, 3 carbon atoms, 4 carbon atoms, etc., up toand including 25 carbon atoms, although the present definition alsocovers the occurrence of the term “alkynyl” where no numerical range isdesignated). The alkynyl group may also be a medium size alkynyl having2 to 15 carbon atoms. The alkynyl group could also be a lower alkynylhaving 2 to 6 carbon atoms. The alkynyl group of the compounds may bedesignated as “C₄” or “C₂-C₄ alkyl” or similar designations. An alkynylgroup may be unsubstituted or substituted.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group, or a C₆ aryl group(although the definition of C₆-C₁₀ aryl covers the occurrence of “aryl”when no numerical range is designated). Examples of aryl groups include,but are not limited to, benzene, naphthalene and azulene. An aryl groupmay be substituted or unsubstituted.

As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl groupconnected, as a substituent, via a lower alkylene group. The aralkylgroup may have 6 to 20 carbon atoms (whenever it appears herein, anumerical range such as “6 to 20” refers to each integer in the givenrange; e.g., “6 to 20 carbon atoms” means that the aralkyl group mayconsist of 6 carbon atom, 7 carbon atoms, 8 carbon atoms, etc., up toand including 20 carbon atoms, although the present definition alsocovers the occurrence of the term “aralkyl” where no numerical range isdesignated). The lower alkylene and aryl group of an aralkyl may besubstituted or unsubstituted. Examples include but are not limited tobenzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

“Lower alkylene groups” refer to a C₁-C₂₅ straight-chained alkyltethering groups, such as —CH₂— tethering groups, forming bonds toconnect molecular fragments via their terminal carbon atoms. Examplesinclude but are not limited to methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and butylene (—CH₂CH₂CH₂CH₂—). A lower alkylenegroup can be substituted by replacing one or more hydrogen of the loweralkylene group with a substituent(s) listed under the definitionof“substituted.”

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused fashion. Cycloalkyl groups can contain 3 to 10 atoms in thering(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may beunsubstituted or substituted. Typical cycloalkyl groups include, but arein no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

As used herein, “cycloalkenyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more double bonds in atleast one ring; although, if there is more than one, the double bondscannot form a fully delocalized pi-electron system throughout all therings (otherwise the group would be “aryl,” as defined herein). Whencomposed of two or more rings, the rings may be connected together in afused fashion. A cycloalkenyl group may be unsubstituted or substituted.

As used herein, “cycloalkynyl” refers to a mono- or multi-cyclichydrocarbon ring system that contains one or more triple bonds in atleast one ring. If there is more than one triple bond, the triple bondscannot form a fully delocalized pi-electron system throughout all therings. When composed of two or more rings, the rings may be joinedtogether in a fused fashion. A cycloalkynyl group may be unsubstitutedor substituted.

As used herein, “alkoxy” or “alkyloxy” refers to the formula —OR whereinR is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or acycloalkynyl as defined above. A non-limiting list of alkoxys aremethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy and tert-butoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl,aryl, or heteroaryl connected, as substituents, via a carbonyl group.Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acylmay be substituted or unsubstituted.

As used herein, “alkoxyalkyl” or “alkyloxyalkyl” refers to an alkoxygroup connected, as a substituent, via a lower alkylene group. Examplesinclude alkyl-O-alkyl- and alkoxy-alkyl- with the terms alkyl and alkoxydefined herein.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkylmay be substituted or unsubstituted.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl and tri-haloalkyl). Such groups include butare not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoromethyl, 2-fluoroisobutyl. Ahaloalkyl may be substituted or unsubstituted.

The term “amino” as used herein refers to a —NH₂ group.

As used herein, the term “hydroxy” refers to a —OH group.

A “cyano” group refers to a “—CN” group.

A “carbonyl” or an “oxo” group refers to a C═O group.

The term “azido” as used herein refers to a —N₃ group.

As used herein, “aminoalkyl” refers to an amino group connected, as asubstituent, via a lower alkylene group. Examples include H₂N-alkyl-with the term alkyl defined herein.

As used herein, “alkylcarboxyalkyl” refers to an alkyl group connected,as a substituent, to a carboxy group that is connected, as asubstituent, to an alkyl group. Examples include alkyl-C(═O)O-alkyl- andalkyl-O—C(═O)-alkyl- with the term alkyl as defined herein.

As used herein, “alkylaminoalkyl” refers to an alkyl group connected, asa substituent, to an amino group that is connected, as a substituent, toan alkyl group. Examples include alkyl-NH-alkyl-, with the term alkyl asdefined herein.

As used herein, “dialkylaminoalkyl” or “di(alkyl)aminoalkyl” refers totwo alkyl groups connected, each as a substituent, to an amino groupthat is connected, as a substituent, to an alkyl group. Examples include

with the term alkyl as defined herein.

As used herein, “alkylaminoalkylamino” refers to an alkyl groupconnected, as a substituent, to an amino group that is connected, as asubstituent, to an alkyl group that is connected, as a substituent, toan amino group. Examples include alkyl-NH-alkyl-NH—, with the term alkylas defined herein.

As used herein, “alkylaminoalkylaminoalkylamino” refers to an alkylgroup connected, as a substituent, to an amino group that is connected,as a substituent, to an alkyl group that is connected, as a substituent,to an amino group that is connected, as a substituent, to an alkylgroup. Examples include alkyl-NH-alkyl-NH-alkyl-, with the term alkyl asdefined herein.

As used herein, “arylaminoalkyl” refers to an aryl group connected, as asubstituent, to an amino group that is connected, as a substituent, toan alkyl group. Examples include aryl-NH-alkyl-, with the terms aryl andalkyl as defined herein.

As used herein, “aminoalkyloxy” refers to an amino group connected, as asubstituent, to an alkyloxy group. Examples include H₂N-alkyl-O— andH₂N-alkoxy- with the terms alkyl and alkoxy as defined herein.

As used herein, “aminoalkyloxyalkyl” refers to an amino group connected,as a substituent, to an alkyloxy group connected, as a substituent, toan alkyl group. Examples include H2N-alkyl-O-alkyl- andH₂N-alkoxy-alkyl- with the terms alkyl and alkoxy as defined herein.

As used herein, “aminoalkylcarboxy” refers to an amino group connected,as a substituent, to an alkyl group connected, as a substituent, to acarboxy group. Examples include H₂N-alkyl-C(═O)O— and H₂N-alkyl-O—C(═O)—with the term alkyl as defined herein.

As used herein, “aminoalkylaminocarbonyl” refers to an amino groupconnected, as a substituent, to an alkyl group connected, as asubstituent, to an amino group connected, as a substituent, to acarbonyl group. Examples include H₂N-alkyl-NH—C(═O)— with the term alkylas defined herein.

As used herein, “aminoalkylcarboxamido” refers to an amino groupconnected, as a substituent, to an alkyl group connected, as asubstituent, to a carbonyl group connected, as a substituent to an aminogroup. Examples include H₂N-alkyl-C(═O)—NH— with the term alkyl asdefined herein.

As used herein, “azidoalkyloxy” refers to an azido group connected as asubstituent, to an alkyloxy group. Examples include N₃-alkyl-O— andN₃-alkoxy- with the terms alkyl and alkoxy as defined herein.

As used herein, “cyanoalkyloxy” refers to a cyano group connected as asubstituent, to an alkyloxy group. Examples include NC-alkyl-O— andNC-alkoxy- with the terms alkyl and alkoxy as defined herein.

As used herein, “guanidinoalkyloxy” refers to a guanidinyl groupconnected, as a substituent, to an alkyloxy group. Examples include

with the terms alkyl and alkoxy as defined herein.

As used herein, “guanidinoalkylcarboxy” refers to a guanidinyl groupconnected, as a substituent, to an alkyl group connected, as asubstituent, to a carboxy group. Examples include

with the term alkyl as defined herein.

As used herein, “quaternary ammonium alkylcarboxy” refers to aquaternized amino group connected, as a substituent, to an alkyl groupconnected, as a substituent, to a carboxy group. Examples include

with the term alkyl as defined herein.

The term “halogen atom” or “halogen” as used herein, means any one ofthe radio-stable atoms of column 7 of the Periodic Table of theElements, such as, fluorine, chlorine, bromine and iodine.

Where the numbers of substituents is not specified (e.g. haloalkyl),there may be one or more substituents present. For example “haloalkyl”may include one or more of the same or different halogens.

As used herein, the term “amino acid” refers to any amino acid (bothstandard and non-standard amino acids), including, but not limited to,α-amino acids, β-amino acids, γ-amino acids and 6-amino acids. Examplesof suitable amino acids include, but are not limited to, alanine,asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline,serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, threonine, tryptophan and valine. Additionalexamples of suitable amino acids include, but are not limited to,ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine,gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine,alpha-propyl-glycine and norleucine.

A linking group is a divalent moiety used to link one steroid to anothersteroid. In some embodiments, the linking group is used to link a firstCSA with a second CSA (which may be the same or different). An exampleof a linking group is (C₁-C₁₀) alkyloxy-(C₁-C₁₀) alkyl.

The terms “P.G.” or “protecting group” or “protecting groups” as usedherein refer to any atom or group of atoms that is added to a moleculein order to prevent existing groups in the molecule from undergoingunwanted chemical reactions. Examples of protecting group moieties aredescribed in T. W. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J. F. W.McOmie, Protective Groups in Organic Chemistry Plenum Press, 1973, bothof which are hereby incorporated by reference for the limited purpose ofdisclosing suitable protecting groups. The protecting group moiety maybe chosen in such a way, that they are stable to certain reactionconditions and readily removed at a convenient stage using methodologyknown from the art. A non-limiting list of protecting groups includebenzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g.,t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls andarylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether(e.g. methoxymethyl ether); substituted ethyl ether; a substitutedbenzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl,triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl ort-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g.methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclicketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane,1,3-dioxolanes, and those described herein); acyclic acetal; cyclicacetal (e.g., those described herein); acyclic hemiacetal; cyclichemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane);orthoesters (e.g., those described herein) and triarylmethyl groups(e.g., trityl; monomethoxytrityl (MMTr); 4,4′-dimethoxytrityl (DMTr);4,4′,4″-trimethoxytrityl (TMTr); and those described herein).Amino-protecting groups are known to those skilled in the art. Ingeneral, the species of protecting group is not critical, provided thatit is stable to the conditions of any subsequent reaction(s) on otherpositions of the compound and can be removed at the appropriate pointwithout adversely affecting the remainder of the molecule. In addition,a protecting group may be substituted for another after substantivesynthetic transformations are complete. Clearly, where a compounddiffers from a compound disclosed herein only in that one or moreprotecting groups of the disclosed compound has been substituted with adifferent protecting group, that compound is within the disclosure.

Compounds:

Compounds useful in accordance with this disclosure are describedherein, both generically and with particularity, and in U.S. Pat. Nos.6,350,738, 6,486,148, 6,767,904, 7,598,234, and 7,754,705, which areincorporated herein by reference. Compounds include steroid derivatives,such as cationic steroid antimicrobials (“CSAs”) that exhibit one ormore anti-cancer and/or anti-proliferative activities or functions. Theskilled artisan will recognize the compounds within the generic formulaset forth herein. Additional compounds of the disclosure having one ormore anti-cancer and/or anti-proliferative activities or functions aredescribed and can be characterized using the assays set forth herein andin the art. Methods and Uses:

Disclosed herein are methods of treating cancer comprising identifying apatient in need of treatment and administering a therapeuticallyeffective amount of at least one cationic steroid antimicrobial (CSA),or a pharmaceutically acceptable salt thereof. Disclosed herein are alsomethods of reducing cellular proliferation comprising contacting acationic steroid antimicrobial (CSA) with a cell selected from the groupconsisting of: CCRF-CEM; HL-60(TB); K-562; MOLT-4; RPMI-8226; SR;A549/ATCC; EKVX; HOP-62; HOP-92; NCI-H226; NCI-H23; NCI-H322M; NCI-H460;NCI-H522; COLO 205; HCC-2998; HCT-116; HCT-15; HT29; KM12; SW-620;SF-268; SF-295; SF-539; SNB-19; SNB-75; U251; LOX IMVI; MALME-3M; M14;SK-MEL-2; SK-MEL-28; SK-MEL-5; UACC-257; UACC-62; IGROV1; OVCAR-3;OVCAR-4; OVCAR-5; OVCAR-8; NCI/ADR-RES; SK-OV-3; 786-0; A4981; ACHN;CAKI-1; RXF 393; SN12C; TK-10; UO-31; PC-3; DU-145; MCF7; NCI-ADR-RES;MDA-MB-231/ATCC; HS 578T; MDA-MB-435; MDA-MB-468; BT-549; and T-47D.Also contemplated is treating a cancer patient having cancer of a typerepresented by or characterized by one of the foregoing cell lines, byadministering an effective anti-cancer amount of a CSA to the patient.

In some embodiments, the cancer is leukemia, non-small cell lung cancer,colon cancer, CNS cancer, skin cancer, ovarian cancer, renal cancer,prostate cancer, breast cancer, or multiple myeloma. In otherembodiments, the skin cancer is melanoma.

Some embodiments disclosed herein relate to a method of treating cancerand/or reducing cellular proliferation by administering a compound ofFormula (I) or a pharmaceutically acceptable salt thereof:

wherein rings A, B, C, and D are independently saturated, or are fullyor partially unsaturated, provided that at least two of rings A, B, C,and D are saturated; m, n, p, and q are independently 0 or 1; R₁ throughR₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ are independently selected fromthe group consisting of hydrogen, hydroxyl, a substituted orunsubstituted alkyl, substituted or unsubstituted hydroxyalkyl,substituted or unsubstituted alkyloxyalkyl, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkyl,substituted or unsubstituted alkylaminoalkylamino, substituted orunsubstituted alkylaminoalkylaminoalkylamino, a substituted orunsubstituted aminoalkyl, a substituted or unsubstituted aryl, asubstituted or unsubstituted arylaminoalkyl, substituted orunsubstituted haloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, oxo, a linking group attached to asecond steroid, a substituted or unsubstituted aminoalkyloxy, asubstituted or unsubstituted aminoalkyloxyalkyl, a substituted orunsubstituted aminoalkylcarboxy, a substituted or unsubstitutedaminoalkylaminocarbonyl, a substituted or unsubstitutedaminoalkylcarboxamido, a substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,substituted or unsubstituted azidoalkyloxy, substituted or unsubstitutedcyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstitutedguanidinoalkyloxy, substituted or unsubstituted quaternary ammoniumalkylcarboxy, and substituted or unsubstituted guanidinoalkyl carboxy,where Q₅ is a side chain of any amino acid (including a side chain ofglycine, i.e., H), and P.G. is an amino protecting group; and R₅, R₈,R₉, R₁₀, R₁₃, R₁₄ and R₁₇ are independently deleted when one of rings A,B, C, or D is unsaturated so as to complete the valency of the carbonatom at that site, or R₅, R₈, R₉, R₁₀, R₁₃, and R₁₄ are independentlyselected from the group consisting of hydrogen, hydroxyl, a substitutedor unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl,substituted or unsubstituted alkyloxyalkyl, a substituted orunsubstituted aminoalkyl, a substituted or unsubstituted aryl,substituted or unsubstituted haloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, oxo, a linking groupattached to a second steroid, a substituted or unsubstitutedaminoalkyloxy, a substituted or unsubstituted aminoalkylcarboxy, asubstituted or unsubstituted aminoalkylaminocarbonyl, a substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, substituted or unsubstituted azidoalkyloxy,substituted or unsubstituted cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—,substituted or unsubstituted guanidinoalkyloxy, and substituted orunsubstituted guanidinoalkylcarboxy, where Q₅ is a side chain of anyamino acid, P.G. is an amino protecting group; provided that at leasttwo or three of R₁₋₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ areindependently selected from the group consisting of a substituted orunsubstituted aminoalkyl, a substituted or unsubstituted aminoalkyloxy,substituted or unsubstituted alkylcarboxyalkyl, substituted orunsubstituted alkylaminoalkylamino, substituted or unsubstitutedalkylaminoalkylaminoalkylamino, a substituted or unsubstitutedaminoalkylcarboxy, a substituted or unsubstituted arylaminoalkyl, asubstituted or unsubstituted aminoalkyloxyaminoalkylaminocarbonyl, asubstituted or unsubstituted aminoalkylaminocarbonyl, a substituted orunsubstituted aminoalkylcarboxyamido, a substituted or unsubstitutedquaternary ammonium alkylcarboxy, a substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,substituted or unsubstituted azidoalkyloxy, substituted or unsubstitutedcyanoalkyloxy, P.G.-HN—HC(Q5)-C(O)—O—, substituted or unsubstitutedguanidinoalkyloxy, and a substituted or unsubstitutedguanidinoalkylcarboxy.

In some embodiments, R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈are independently selected from the group consisting of hydrogen,hydroxyl, a substituted or unsubstituted (C₁-C₁₈) alkyl, substituted orunsubstituted (C₁-C₁₈) hydroxyalkyl, substituted or unsubstituted(C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)alkylcarboxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈)alkyl, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, a substituted orunsubstituted (C₁-C₁₈) aminoalkyl, a substituted or unsubstituted aryl,a substituted or unsubstituted arylamino-(C₁-C₁₈) alkyl, substituted orunsubstituted (C₁-C₁₈) haloalkyl, substituted or unsubstituted (C₂-C₆)alkenyl, substituted or unsubstituted (C₂-C₆) alkynyl, oxo, a linkinggroup attached to a second steroid, a substituted or unsubstituted(C₁-C₁₈) aminoalkyloxy, a substituted or unsubstituted (C₁-C₁₈)aminoalkyloxy-(C₁-C₁₈) alkyl, a substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxy, a substituted or unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, a substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, a substituted or unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, substitutedor unsubstituted (C₁-C₁₈) azidoalkyloxy, substituted or unsubstituted(C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted orunsubstituted (C₁-C₁₈) guanidinoalkyloxy, substituted or unsubstituted(C₁-C₁₈) quaternary ammonium alkylcarboxy, and substituted orunsubstituted (C₁-C₁₈) guanidinoalkyl carboxy, where Q₅ is a side chainof any amino acid (including a side chain of glycine, i.e., H), and P.G.is an amino protecting group; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, a substituted or unsubstituted(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈) hydroxyalkyl,substituted or unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, asubstituted or unsubstituted (C₁-C₁₈) aminoalkyl, a substituted orunsubstituted aryl, substituted or unsubstituted (C₁-C₁₈) haloalkyl,substituted or unsubstituted (C₂-C₆) alkenyl, substituted orunsubstituted (C₂-C₆) alkynyl, oxo, a linking group attached to a secondsteroid, a substituted or unsubstituted (C₁-C₁₈) aminoalkyloxy, asubstituted or unsubstituted (C₁-C₁₈) aminoalkylcarboxy, a substitutedor unsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, substitutedor unsubstituted (C₁-C₁₈) azidoalkyloxy, substituted or unsubstituted(C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted orunsubstituted (C₁-C₁₈) guanidinoalkyloxy, and substituted orunsubstituted (C₁-C₁₈) guanidinoalkylcarboxy, where Q5 is a side chainof any amino acid, and P.G. is an amino protecting group; provided thatat least two or three of R₁₋₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈are independently selected from the group consisting of a substituted orunsubstituted (C₁-C₁₈) aminoalkyl, a substituted or unsubstituted(C₁-C₁₈) aminoalkyloxy, substituted or unsubstituted (C₁-C₁₈)alkylcarboxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino (C₁-C₁₈) alkylamino, a substituted orunsubstituted (C₁-C₁₈) aminoalkylcarboxy, a substituted or unsubstitutedarylamino (C₁-C₁₈) alkyl, a substituted or unsubstituted (C₁-C₁₈)aminoalkyloxy (C₁-C₁₈) aminoalkylaminocarbonyl, a substituted orunsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, a substituted orunsubstituted (C₁-C₁₈) aminoalkylcarboxyamido, a substituted orunsubstituted (C₁-C₁₈) quaternary ammonium alkylcarboxy, substituted orunsubstituted di(C₁-C₁₈ alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, substituted or unsubstituted (C₁-C₁₈)azidoalkyloxy, substituted or unsubstituted (C₁-C₈) cyanoalkyloxy,P.G.-HN—HC(Q5)-C(O)—O—, substituted or unsubstituted (C₁-C₁₈)guanidinoalkyloxy, and a substituted or unsubstituted (C₁-C₁₈)guanidinoalkylcarboxy.

In some embodiments, R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈are independently selected from the group consisting of hydrogen,hydroxyl, an unsubstituted (C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)hydroxyalkyl, unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈) alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; provided that at least two or three of R₁₋₄, R₆,R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from thegroup consisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy.

In some embodiments, the CSA, or pharmaceutically acceptable saltsthereof of Formula (I), can be also represented by Formula (II):

In some embodiments, rings A, B, C, and D are independently saturated.

In some embodiments, one or more of rings A, B, C, and D areheterocyclic.

In some embodiments, rings A, B, C, and D are non-heterocyclic.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of hydrogen, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted arylamino-(C₁-C₁₈) alkyl, anunsubstituted (C₁-C₁₈) aminoalkyloxy, an unsubstituted (C₁-C₁₈)aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxy, an unsubstituted (C₁-C₁₈) aminoalkylaminocarbonyl, anunsubstituted (C₁-C₁₈) aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, unsubstituted (C₁-C₁₈) guanidinoalkyloxy,unsubstituted (C₁-C₁₈) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-C₁₈) guanidinoalkyl carboxy; and R₁, R₂, R₄, R₅, R₆,R₈, R₉, R₁₀, R₁₁, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ are independently selectedfrom the group consisting of hydrogen and unsubstituted (C₁-C₆) alkyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of hydrogen, an unsubstituted (C₁-C₆) alkyl,unsubstituted (C₁-C₆) hydroxyalkyl, unsubstituted (C₁-C₁₆)alkyloxy-(C₁-C₅) alkyl, unsubstituted (C₁-C₁₆) alkylcarboxy-(C₁-C₅)alkyl, unsubstituted (C₁-C₁₆) alkylamino-(C₁-C₅)alkyl, unsubstituted(C₁-C₁₆) alkylamino-(C₁-C₅) alkylamino, unsubstituted (C₁-C₁₆)alkylamino-(C₁-C₁₆) alkylamino-(C₁-C₅) alkylamino, an unsubstituted(C₁-C₁₆) aminoalkyl, an unsubstituted arylamino-(C₁-C₅) alkyl, anunsubstituted (C₁-C₅) aminoalkyloxy, an unsubstituted (C₁-C₁₆)aminoalkyloxy-(C₁-C₅) alkyl, an unsubstituted (C₁-C₅) aminoalkylcarboxy,an unsubstituted (C₁-C₅) aminoalkylaminocarbonyl, an unsubstituted(C₁-C₅) aminoalkylcarboxamido, an unsubstituted di(C₁-C₅alkyl)amino-(C₁-C₅) alkyl, unsubstituted (C₁-C₅) guanidinoalkyloxy,unsubstituted (C₁-C₁₆) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-C₁₆) guanidinoalkylcarboxy;

In some embodiments, R₁, R₂, R₄, R₅, R₆, R₈, R₁₀, R₁₁, R₁₄, R₁₆, and R₁₇are each hydrogen; and R₉ and R₁₃ are each methyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of aminoalkyloxy; aminoalkylcarboxy;alkylaminoalkyl; alkoxycarbonylalkyl; alkylcarbonylalkyl;di(alkyl)aminoalkyl; alkoxycarbonylalkyl; and alkylcarboxyalkyl.

In some embodiments, R₃, R₇, and R₁₂ are independently selected from thegroup consisting of aminoalkyloxy and aminoalkylcarboxy; and R₁₈ isselected from the group consisting of alkylaminoalkyl;alkoxycarbonylalkyl; alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl;alkylaminoalkyl; alkyoxycarbonylalkyl; and alkylcarboxyalkyl.

In some embodiments, R₃, R₇, and R₁₂ are the same.

In some embodiments, R₃, R₇, and R₁₂ are aminoalkyloxy.

In some embodiments, R₃, R₇, and R₁₂ are aminoalkylcarboxy.

In some embodiments, R₁₈ is alkylaminoalkyl.

In some embodiments, R₁₈ is alkoxycarbonylalkyl.

In some embodiments, R₁₈ is di(alkyl)aminoalkyl.

In some embodiments, R₁₈ is alkylcarboxyalkyl.

In some embodiments, R₃, R₇, R₁₂, and R₁₈ are independently selectedfrom the group consisting of amino-C₃-alkyloxy; amino-C₃-alkyl-carboxy;C₈-alkylamino-C₅-alkyl; C₈-alkoxy-carbonyl-C₄-alkyl;C₈-alkyl-carbonyl-C₄-alkyl; di-(C₅-alkyl)amino-C₅-alkyl;C₁₃-alkylamino-C₅-alkyl; C₆-alkoxy-carbonyl-C₄-alkyl;C₆-alkyl-carboxy-C₄-alkyl; and C₁₆-alkylamino-C₅-alkyl.

In some embodiments, m, n, and p are each 1 and q is 0.

In some embodiments, the CSA, or pharmaceutically acceptable saltsthereof of Formula (I) can be also represented by Formula (III):

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is:

In some embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

In other embodiments, the CSA, or a pharmaceutically acceptable saltthereof, is

Pharmaceutically Acceptable Salts

The compounds and compositions disclosed herein are optionally preparedas pharmaceutically acceptable salts. The term “pharmaceuticallyacceptable salt” as used herein is a broad term, and is to be given itsordinary and customary meaning to a skilled artisan (and is not to belimited to a special or customized meaning), and refers withoutlimitation to a salt of a compound that does not cause significantirritation to an organism to which it is administered and does notabrogate the biological activity and properties of the compound. In someembodiments, the salt is an acid addition salt of the compound.Pharmaceutical salts can be obtained by reacting a compound withinorganic acids such as hydrohalic acid (e.g., hydrochloric acid orhydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid.Pharmaceutical salts can also be obtained by reacting a compound with anorganic acid such as aliphatic or aromatic carboxylic or sulfonic acids,for example formic acid, acetic acid, propionic acid, glycolic acid,pyruvic acid, malonic acid, maleic acid, fumaric acid, trifluoroaceticacid, benzoic acid, cinnamic acid, mandelic acid, succinic acid, lacticacid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinicacid, methanesulfonic acid, ethanesulfonic acid, p-toluensulfonic acid,salicylic acid, stearic acid, muconic acid, butyric acid, phenylaceticacid, phenylbutyric acid, valproic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid, or naphthalenesulfonic acid. Pharmaceuticalsalts can also be obtained by reacting a compound with a base to form asalt such as an ammonium salt, an alkali metal salt, such as a lithium,sodium or a potassium salt, an alkaline earth metal salt, such as acalcium, magnesium or aluminum salt, a salt of organic bases such asdicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine,C₁-C₇ alkylamine, cyclohexylamine, dicyclohexylamine, triethanolamine,ethylenediamine, ethanolamine, diethanolamine, triethanolamine,tromethamine, and salts with amino acids such as arginine and lysine; ora salt of an inorganic base, such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, orthe like.

In some embodiments, the pharmaceutically acceptable salt is ahydrochloride salt. In some embodiments, the pharmaceutically acceptablesalt is a mono-hydrochloride salt, a di-hydrochloride salt, atri-hydrochloride salt, or a tetra-hydrochloride salt.

Co-Administration:

As used herein, “co-administration” means concurrently or administeringone substance followed by beginning the administration of a secondsubstance within 24 hours, 20 hours, 16 hours, 12 hours, 8 hours, 4hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, 1 minute, a rangebounded by any two of the aforementioned numbers, and/or about any ofthe aforementioned numbers.

In some embodiments, one or more CSAs are co-administered. In otherembodiments, the co-administration of CSAs accounts for theirtherapeutic benefit. In some embodiments, co-administration isconcurrent.

In some embodiments, non-CSA chemotherapeutic agents are administered tothe patient. In some embodiments, the non-CSA chemotherapeutic agentsare co-administered. Such chemotherapeutic agents include, but are notlimited to, a regulatory agency approved chemotherapeutic agent. In someembodiments, the regulatory agency is the Food and Drug Administration(FDA).

In some embodiments, the non-CSA chemotherapeutic agent is selected fromthe group consisting of alkylating agents, anthracyclines, cytoskeletaldisruptors, epothilones, histone deacetylase inhibitors, topoisomeraseinhibitors, kinase inhibitors, monoclonal antibodies, nucleotideanalogs, peptide antibiotics, platinum-based agents, retinoids, andvinca alkaloids. Such agents are known in the art, for example,actinomycin, all-trans retinoic acid, azacitidine, azathioprine,bleomycin, bortezomib, camptothecin, carboplatin, capecitabine,cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin,docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone,etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib,irinotecan, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone,oxaliplatin, paclitaxel, pemetrexed, teniposide, tioguanine, topotecan,valrubicin, vinblastine, vincristine, vindesine, and vinorelbine.

Multi-drug resistance of cancer cells can prevent successfulchemotherapy. Various mechanisms of drug resistance are known, includingthe ABC transporters that can remove drugs from the cells. Efflux pumpinhibitors can be overexpressed in cancer and contribute to drugresistance. Co-administration of the CSA therapeutic with an effectiveamount of an efflux pump inhibitor, such as an ABC transport inhibitor(e.g., ABCG2) is specifically contemplated. For example, humancathelicidin or other cathelicidin could be administered in conjunctionwith a CSA to more effectively treat drug resistance mediated by effluxpump activity, such as ABCG2, thereby sensitizing the cancer cells tochemotherapy. In addition, any other sensitizing agent could be used.

In some embodiments, one or more CSAs are co-administered topermeabilize a cell membrane. Such permeabilization can sensitize cancercells to chemotherapy by overcoming the effect of efflux pumps and allowtherapeutic levels of anti-cancer agents to accumulate in the cell. Suchco-administration may allow for the use of lower doses of anti-canceragentsm thereby minimizing adverse side effects. In some embodiments,the anti-cancer agent is also a CSA. In other embodiments, a single CSAis administered and responsible for both anti-cancer and cellpermeabilization effects.

Many cancer therapies are also immunosuppressive, and a common sideeffect of existing cancer therapies is infection. In some embodiments,one or more CSAs are co-administered to prevent or minimize infectionsduring cancer treatment. Such action may be in addition to otherbeneficial actions against the cancer cells. In some embodiments, one ormore CSAs are co-administered such that the effect is upregulation ofthe patient's immune system, thereby allowing the patient to counteractcancer indirectly from the administration of the CSA. In someembodiments, one or more CSAs are co-administered such that the CSAs arenot directly toxic to cancer cells but improve the patient's immunestatus to help the patient counteract cancer and/or also help preventmetastases. In some embodiments, the same CSA is responsible for bothanti-cancer and anti-infective effects. In other embodiments, the sameCSA is responsible for both anti-cancer effects and upregulation of thepatient's immune system.

In some embodiments, therapeutics are administered to alleviate one ormore side effects of cancer treatment. In some embodiments, theadministration is concurrent. As a non-limiting example, in someembodiments, anti-nausea/vomiting medicines are administered. Suchmedicines are known in the art and include Alprazolam; Aprepitant;Dexamethasone; Diphenhydramine; Dolasetron; Dronabinol; Granisetron;Haloperidol; Lorazepam; Metoclopramide; Nabilone; Ondansetron;Olanzapine; Palonosetron; Prochlorperazine; and Promethazine.

In some embodiments, therapeutics are administered to alleviate one ormore symptoms of cancer. In some embodiments, the administration isconcurrent. Non-limiting examples of symptoms include pain, loss ofappetite, and depression. Medicines that alleviate these symptoms areknown in the art and include, non-opioids such as acetaminophen,aspirin, and ibuprofen; opioids such as morphine, fentanyl,hydromorphone, oxycodone, and codeine; steroids such as prednisone anddexamethasone; and, for tingling or burning pain, antidepressants suchas amitriptyline, nortriptyline, and desipramine and anti-convulsantssuch as carbamazepine, gabapentin, and phenytoin.

Some embodiments are directed to the use of companion diagnostics toidentify an appropriate treatment for the patient. A companiondiagnostic is an in vitro diagnostic test or device that providesinformation that is essential for the safe and effective use of acorresponding therapeutic product. Such tests or devices can identifypatients likely to be at risk for adverse reactions as a result oftreatment with a particular therapeutic product. Such tests or devicescan also monitor responsiveness to treatment (or estimate responsivenessto possible treatments). Such monitoring may include schedule, dose,discontinuation, or combinations of therapeutic agents. In someembodiments, the CSA is selected by measuring a biomarker in thepatient. The term biomarker includes, but is not limited to, geneticregulation, protein levels, RNA levels, and cellular responses such ascytotoxicity. In some embodiments, one or more chemotherapeutic agentsare selected by subjecting a sample from the patient to a companiondiagnostic device. In some embodiments, the sample is a tissue sample.In other embodiments, the tissue sample is representative of the cancerto be treated. In some embodiments, the tissue sample contains a portionof the cancer to be treated. In some embodiments, the tissue sample isnot cancerous.

Pharmaceutical Compositions

While it is possible for the compounds described herein to beadministered alone, it may be preferable to formulate the compounds aspharmaceutical compositions. As such, in yet another aspect,pharmaceutical compositions useful in the methods and uses of thedisclosed embodiments are provided. More particularly, thepharmaceutical compositions described herein may be useful, inter alia,for treating or preventing a bone disease and/or a broken bone. Apharmaceutical composition is any composition that may be administeredin vitro or in vivo or both to a subject in order to treat or amelioratea condition. In a preferred embodiment, a pharmaceutical composition maybe administered in vivo. A subject may include one or more cells ortissues, or organisms. In some exemplary embodiments, the subject is ananimal. In some embodiments, the animal is a mammal. The mammal may be ahuman or primate in some embodiments. A mammal includes any mammal, suchas by way of non-limiting example, cattle, pigs, sheep, goats, horses,camels, buffalo, cats, dogs, rats, mice, and humans.

As used herein the terms “pharmaceutically acceptable” and“physiologically acceptable” mean a biologically compatible formulation,gaseous, liquid or solid, or mixture thereof, which is suitable for oneor more routes of administration, in vivo delivery, or contact. Aformulation is compatible in that it does not destroy activity of anactive ingredient therein (e.g., a CSA), or induce adverse side effectsthat far outweigh any prophylactic or therapeutic effect or benefit.

In an embodiment, the pharmaceutical compositions may be formulated withpharmaceutically acceptable excipients such as carriers, solvents,stabilizers, adjuvants, diluents, etc., depending upon the particularmode of administration and dosage form. The pharmaceutical compositionsshould generally be formulated to achieve a physiologically compatiblepH, and may range from a pH of about 3 to a pH of about 11, preferablyabout pH 3 to about pH 7, depending on the formulation and route ofadministration. In alternative embodiments, it may be preferred that thepH is adjusted to a range from about pH 5.0 to about pH 8. Moreparticularly, the pharmaceutical compositions may comprise atherapeutically or prophylactically effective amount of at least onecompound as described herein, together with one or more pharmaceuticallyacceptable excipients. Optionally, the pharmaceutical compositions maycomprise a combination of the compounds described herein, or may includea second active ingredient useful in the treatment or prevention ofbacterial infection (e.g., anti-bacterial or anti-microbial agents).

Formulations, e.g., for parenteral or oral administration, are mosttypically solids, liquid solutions, emulsions or suspensions, whileinhalable formulations for pulmonary administration are generallyliquids or powders, with powder formulations being generally preferred.A preferred pharmaceutical composition may also be formulated as alyophilized solid that is reconstituted with a physiologicallycompatible solvent prior to administration. Alternative pharmaceuticalcompositions may be formulated as syrups, creams, ointments, tablets,and the like.

Compositions may contain one or more excipients. Pharmaceuticallyacceptable excipients are determined in part by the particularcomposition being administered, as well as by the particular method usedto administer the composition. Accordingly, there exists a wide varietyof suitable formulations of pharmaceutical compositions (see, e.g.,Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants such as ascorbic acid; chelating agents such as EDTA;carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water,saline, glycerol and ethanol; wetting or emulsifying agents; pHbuffering substances; and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions described herein may be formulated inany form suitable for the intended method of administration. Whenintended for oral use for example, tablets, troches, lozenges, aqueousor oil suspensions, non-aqueous solutions, dispersible powders orgranules (including micronized particles or nanoparticles), emulsions,hard or soft capsules, syrups or elixirs may be prepared. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents including sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a palatable preparation.

Pharmaceutically acceptable excipients particularly suitable for use inconjunction with tablets include, for example, inert diluents, such ascelluloses, calcium or sodium carbonate, lactose, calcium or sodiumphosphate; disintegrating agents, such as cross-linked povidone, maizestarch, or alginic acid; binding agents, such as povidone, starch,gelatin or acacia; and lubricating agents, such as magnesium stearate,stearic acid or talc.

Tablets may be uncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In another embodiment, pharmaceutical compositions may be formulated assuspensions comprising a compound of the embodiments in admixture withat least one pharmaceutically acceptable excipient suitable for themanufacture of a suspension.

In yet another embodiment, pharmaceutical compositions may be formulatedas dispersible powders and granules suitable for preparation of asuspension by the addition of suitable excipients.

Excipients suitable for use in connection with suspensions includesuspending agents, such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wettingagents such as a naturally occurring phosphatide (e.g., lecithin), acondensation product of an alkylene oxide with a fatty acid (e.g.,polyoxyethylene stearate), a condensation product of ethylene oxide witha long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), acondensation product of ethylene oxide with a partial ester derived froma fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitanmonooleate); polysaccharides and polysaccharide-like compounds (e.g.dextran sulfate); glycoaminoglycans and glycosaminoglycan-like compounds(e.g., hyaluronic acid); and thickening agents, such as carbomer,beeswax, hard paraffin or cetyl alcohol. The suspensions may alsocontain one or more preservatives such as acetic acid, methyl and/orn-propyl p-hydroxy-benzoate; one or more coloring agents; one or moreflavoring agents; and one or more sweetening agents such as sucrose orsaccharin.

The pharmaceutical compositions may also be in the form of oil-in wateremulsions. The oily phase may be a vegetable oil, such as olive oil orarachis oil, a mineral oil, such as liquid paraffin, or a mixture ofthese. Suitable emulsifying agents include naturally-occurring gums,such as gum acacia and gum tragacanth; naturally occurring phosphatides,such as soybean lecithin, esters or partial esters derived from fattyacids; hexitol anhydrides, such as sorbitan monooleate; and condensationproducts of these partial esters with ethylene oxide, such aspolyoxyethylene sorbitan monooleate. The emulsion may also containsweetening and flavoring agents. Syrups and elixirs may be formulatedwith sweetening agents, such as glycerol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, a flavoringor a coloring agent.

Additionally, the pharmaceutical compositions may be in the form of asterile injectable preparation, such as a sterile injectable aqueousemulsion or oleaginous suspension. This emulsion or suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,2-propane-diol.

The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or diglycerides. In addition, fatty acids such as oleicacid may likewise be used in the preparation of injectables.

To obtain a stable water-soluble dose form of a pharmaceuticalcomposition, a pharmaceutically acceptable salt of a compound describedherein may be dissolved in an aqueous solution of an organic orinorganic acid, such as 0.3 M solution of succinic acid, or morepreferably, citric acid. If a soluble salt form is not available, thecompound may be dissolved in a suitable co-solvent or combination ofco-solvents. Examples of suitable co-solvents include alcohol, propyleneglycol, polyethylene glycol 300, polysorbate 80, glycerin and the likein concentrations ranging from about 0 to about 60% of the total volume.In one embodiment, the active compound is dissolved in DMSO and dilutedwith water.

The pharmaceutical composition may also be in the form of a solution ofa salt form of the active ingredient in an appropriate aqueous vehicle,such as water or isotonic saline or dextrose solution. Also contemplatedare compounds which have been modified by substitutions or additions ofchemical or biochemical moieties which make them more suitable fordelivery (e.g., increase solubility, bioactivity, palatability, decreaseadverse reactions, etc.), for example by esterification, glycosylation,PEGylation, and complexation.

Many therapeutics have undesirably short half-lives and/or undesirabletoxicity. Thus, the concept of improving half-life or toxicity isapplicable to treatments and fields other than cancer. Pharmaceuticalcompositions can be prepared, however, by complexing the therapeuticwith a biochemical moiety to improve such undesirable properties.Proteins are a particular biochemical moiety that may be complexed witha CSA for administration in a wide variety of applications. In someembodiments, one or more CSAs are complexed with a protein for thetreatment of infection. In other embodiments, one or more CSAs arecomplexed with a protein for the treatment of cancer. In someembodiments, one or more CSAs are complexed with a protein to increasethe CSA's half-life. In other embodiments, one or more CSAs arecomplexed with a protein to decrease the CSA's toxicity. Albumin is aparticularly preferred protein for complexation with a CSA. In someembodiments, the albumin is fat-free albumin.

With respect to the CSA therapeutic, the biochemical moiety forcomplexation can be added to the pharmaceutical composition as 0.25,0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10, 20, 50, or 100 weightequivalents, or a range bounded by any two of the aforementionednumbers, or about any of the numbers. In some embodiments, the weightratio of albumin to CSA is about 18:1 or less, such as about 9:1 orless. In some embodiments, the CSA is coated with albumin.

Alternatively, or in addition, non-biochemical compounds can be added tothe pharmaceutical compositions to reduce the toxicity of thetherapeutic and/or improve the half-life. Such an application is notlimited to anti-cancer treatment, but instead has wide applicability tovarious forms of treatment, such as treating infections or cancer.Suitable amounts and ratios of an additive that can improve toxicity canbe determined via a cellular assay. With respect to the CSA therapeutic,toxicity reducing compounds can be added to the pharmaceuticalcomposition as 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 10,20, 50, or 100 weight equivalents, or a range bounded by any two of theaforementioned numbers, or about any of the numbers. In someembodiments, the toxicity reducing compound is a cocoamphodiacetate suchas Miranol® (disodium cocoamphodiacetate). In other embodiments, thetoxicity reducing compound is an amphoteric surfactant. In someembodiments, the toxicity reducing compound is a surfactant. In otherembodiments, the molar ratio of cocoamphodiacetate to CSA is betweenabout 8:1 and 1:1, preferably about 4:1. In some embodiments, thetoxicity reducing compound is allantoin.

In one embodiment, the compounds described herein may be formulated fororal administration in a lipid-based formulation suitable for lowsolubility compounds. Lipid-based formulations can generally enhance theoral bioavailability of such compounds.

As such, a pharmaceutical composition comprises a therapeutically orprophylactically effective amount of a compound described herein,together with at least one pharmaceutically acceptable excipientselected from the group consisting of-medium chain fatty acids orpropylene glycol esters thereof (e.g., propylene glycol esters of ediblefatty acids such as caprylic and capric fatty acids) andpharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenatedcastor oil.

In an alternative preferred embodiment, cyclodextrins may be added asaqueous solubility enhancers. Preferred cyclodextrins includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin. A particularly preferredcyclodextrin solubility enhancer is hydroxypropyl-o-cyclodextrin (BPBC),which may be added to any of the above-described compositions to furtherimprove the aqueous solubility characteristics of the compounds of theembodiments. In one embodiment, the composition comprises about 0.1% toabout 20% hydroxypropyl-o-cyclodextrin, more preferably about 1% toabout 15% hydroxypropyl-o-cyclodextrin, and even more preferably fromabout 2.5% to about 10% hydroxypropyl-o-cyclodextrin. The amount ofsolubility enhancer employed will depend on the amount of the compoundof the embodiments in the composition.

In some exemplary embodiments, a CSA comprises a multimer (e.g., adimer, trimer, tetramer, or higher order polymer). In some exemplaryembodiments, the CSAs can be incorporated into pharmaceuticalcompositions or formulations. Such pharmaceuticalcompositions/formulations are useful for administration to a subject, invivo or ex vivo. Pharmaceutical compositions and formulations includecarriers or excipients for administration to a subject.

Such formulations include solvents (aqueous or non-aqueous), solutions(aqueous or non-aqueous), emulsions (e.g., oil-in-water orwater-in-oil), suspensions, syrups, elixirs, dispersion and suspensionmedia, coatings, isotonic and absorption promoting or delaying agents,compatible with pharmaceutical administration or in vivo contact ordelivery. Aqueous and non-aqueous solvents, solutions and suspensionsmay include suspending agents and thickening agents. Suchpharmaceutically acceptable carriers include tablets (coated oruncoated), capsules (hard or soft), microbeads, powder, granules andcrystals. Supplementary active compounds (e.g., preservatives,antibacterial, antiviral and antifungal agents) can also be incorporatedinto the compositions.

Cosolvents and adjuvants may be added to the formulation. Non-limitingexamples of cosolvents contain hydroxyl groups or other polar groups,for example, alcohols, such as isopropyl alcohol; glycols, such aspropylene glycol, polyethyleneglycol, polypropylene glycol, glycolether; glycerol; polyoxyethylene alcohols and polyoxyethylene fatty acidesters. Adjuvants include, for example, surfactants such as, soyalecithin and oleic acid; sorbitan esters such as sorbitan trioleate; andpolyvinylpyrrolidone.

A pharmaceutical composition and/or formulation contains a total amountof the active ingredient(s) sufficient to achieve an intendedtherapeutic effect.

The term “packaging material” refers to a physical structure housing oneor more components of the kit. The packaging material can maintain thecomponents sterilely, and can be made of material commonly used for suchpurposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules,vials, tubes, etc.). A kit can contain a plurality of components, e.g.,two or more compounds alone or in combination with an osteogenesis agentor treatment or drug, optionally sterile.

A kit optionally includes a label or insert including a description ofthe components (type, amounts, doses, etc.), instructions for use invitro, in vivo, or ex vivo, and any other components therein. Labels orinserts include “printed matter,” e.g., paper or cardboard, or separateor affixed to a component, a kit or packing material (e.g., a box), orattached to an ampule, tube or vial containing a kit component. Labelsor inserts can additionally include a computer readable medium, such asa disk (e.g., floppy diskette, hard disk, ZIP disk), optical disk suchas CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storagemedia such as RAM and ROM or hybrids of these such as magnetic/opticalstorage media, FLASH media or memory type cards.

One of ordinary skill in the art to which these exemplary embodimentsbelong will understand that the compositions may be administered innumerous ways. For example, administration may mean simply applying thecompositions to a bone directly. In some exemplary embodiments,administration may be enteral, parenteral, or topical. Other exemplaryroutes of administration for contact or in vivo delivery which acompound can optionally be formulated include inhalation, respiration,intubation, intrapulmonary instillation, oral (buccal, sublingual,mucosal), intrapulmonary, rectal, vaginal, intrauterine, intradermal,topical, dermal, parenteral (e.g., subcutaneous, intramuscular,intravenous, intradermal, intraocular, intratracheal and epidural),intranasal, intrathecal, intraarticular, intracavity, transdermal,iontophoretic, ophthalmic, optical (e.g., corneal), intraglandular,intraorgan, and/or intralymphatic.

The delivery forms can be homogeneous, e.g., forms in which thecomposition is in solution, or heterogeneous, e.g., forms in which thecomposition is contained within liposomes or microspheres. The forms canproduce an immediate effect, and can alternatively, or additionally,produce an extended effect. For example, liposomes, or microspheres, orother similar means of providing an extended release of the composition,can be used to extend the period during which the composition is exposedto the targeted area; non-encapsulated compositions can also be providedfor an immediate effect.

In some embodiments, the composition or method includes administering aCSA from a pharmaceutically acceptable device(s) such as bandages,surgical dressings, gauzes, adhesive strips, surgical staples, clips,hemostats, intrauterine devices, sutures, trocars, catheters, tubes, andimplants. In some embodiments, the implant is a pill, pellet, rod,screw, wafer, disc, and/or tablet. The devices can deliver thecomposition to a targeted area for a desired period of time. In someexemplary embodiments, the composition may be incorporated into amedical device coating. In some embodiments, the coating contains 0.1weight %, 1 weight %, 5 weight %, 10 weight %, 15 weight %, 20 weight %,25 weight %, 50 weight %, about any of the aforementioned numbers,and/or a range bounded by any two of the aforementioned numbers.

Devices according to the disclosure can be prepared according to knownmethods, and can include, or be made from, polymeric material. In someinstances, the polymeric material will be an absorbable material and inother instances, a non-absorbable material, or in other instances aresorbable material. Devices can, of course, include absorbable,non-absorbable, resorbable materials, and combinations thereof.

Absorbable materials can be synthetic materials and non-syntheticmaterials. Absorbable synthetic materials include, but are not limitedto, cellulosic polymers, glycolic acid polymers, methacrylate polymers,ethylene vinyl acetate polymers, ethylene vinyl alcohol copolymers,polycaptrolactam, polyacetate, copolymers of lactide and glycolide,polydioxanone, polyglactin, poliglecaprone, polyglyconate,polygluconate, and combinations thereof. Absorbable non-syntheticmaterials include, but are not limited to, catgut, cargile membrane,fascia lata, gelatin, collagen, and combinations thereof.

Nonabsorbable synthetic materials include, but are not limited tonylons, rayons, polyesters, polyolefins, and combinations thereof.Non-absorbable non-synthetic materials include, but are not limited to,silk, dermal silk, cotton, linen, and combinations thereof.

Combinations of the foregoing devices and carriers/vehicles are alsoenvisioned. For example, a CSA gel or ointment can be impregnated into abandage or wound dressing for delivery of the CSA to a targetedlocation. As another example, an implantable absorbable device can beloaded with a CSA material and release the CSA from the device over adesired period. Sustained or controlled release formulations,compositions, or devices can be used. A desired period of delivery canbe, for example, at least about 2, 3, 6, 10, 12, 18, or 24 hours, or 1,2, 4, 8, 12, 20, or 30 days, or 1, 2, 3, 4, 5, 6, or more months, andany value in between. The physical form used to deliver the CSA is notcritical and the choice or design of such devices is well within thelevel of skill of one in the art.

It may be desirable to provide for other conditions in the practice ofthe present methods. For example, it may be desirable to ensure that thetarget region is sufficiently oxygenated; generally, it is sufficientthat atmospheric oxygen be present. It also may be desirable to maintaina desired level of moisture and a particular temperature; in someembodiments, a warm, moist environment is desirable. While not required,it may also be desirable to establish or maintain a sterile environment.

Additionally, it may be desirable to include other therapeuticallybeneficial agents in the formulation. For example, the vehicles orcarriers may also include humectants or moisturizers to maintain adesired moisture level in the treated area. Other possibilities includedrugs such as anesthetics or antibiotics, which provide other desiredeffects. Again, known to serve.

Dosages

The formulations may, for convenience, be prepared or provided as a unitdosage form. Preparation techniques include bringing into associationthe active ingredient (e.g., CSA) and a pharmaceutical carrier(s) orexcipient(s). In general, formulations are prepared by uniformly andintimately associating the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product. For example, a tablet may be made by compression ormolding. Compressed tablets may be prepared by compressing, in asuitable machine, an active ingredient (e.g., a CSA) in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Molded tablets may be produced by molding, in a suitableapparatus, a mixture of powdered compound (e.g., CSA) moistened with aninert liquid diluent. The tablets may optionally be coated or scored andmay be formulated so as to provide a slow or controlled release of theactive ingredient therein.

Compounds (e.g., CSAs), including pharmaceutical formulations can bepackaged in unit dosage forms for ease of administration and uniformityof dosage. A “unit dosage form” as used herein refers to a physicallydiscrete unit suited as unitary dosages for the subject to be treated;each unit containing a predetermined quantity of compound optionally inassociation with a pharmaceutical carrier (excipient, diluent, vehicleor filling agent) which, when administered in one or more doses, iscalculated to produce a desired effect (e.g., prophylactic ortherapeutic effect or benefit). Unit dosage forms can contain a dailydose or unit, daily sub-dose, or an appropriate fraction thereof, of anadministered compound (e.g., CSA). Unit dosage forms also include, forexample, capsules, troches, cachets, lozenges, tablets, ampules andvials, which may include a composition in a freeze-dried or lyophilizedstate; a sterile liquid carrier, for example, can be added prior toadministration or delivery in vivo. Unit dosage forms additionallyinclude, for example, ampules and vials with liquid compositionsdisposed therein. Unit dosage forms further include compounds fortransdermal administration, such as “patches” that contact with theepidermis of the subject for an extended or brief period of time. Theindividual unit dosage forms can be included in multi-dose kits orcontainers. Pharmaceutical formulations can be packaged in single ormultiple unit dosage forms for ease of administration and uniformity ofdosage.

Compounds (e.g., CSAs) can be administered in accordance with themethods at any frequency as a single bolus or multiple dose e.g., one,two, three, four, five, or more times hourly, daily, weekly, monthly, orannually or between about 1 to 10 days, weeks, months, or for as long asappropriate. Exemplary frequencies are typically from 1-7 times, 1-5times, 1-3 times, 2-times or once, daily, weekly or monthly. Timing ofcontact, administration ex vivo or in vivo delivery can be dictated bythe infection, pathogenesis, symptom, pathology or adverse side effectto be treated. For example, an amount can be administered to the subjectsubstantially contemporaneously with, or within about 1-60 minutes orhours of the onset of a symptom or adverse side effect, pathogenesis, orvaccination. Long-acting pharmaceutical compositions may be administeredtwice a day, once a day, once every two days, three times a week, twicea week, every 3 to 4 days, or every week depending on half-life andclearance rate of the particular formulation. For example, in anembodiment, a pharmaceutical composition contains an amount of acompound as described herein that is selected for administration to apatient on a schedule selected from: twice a day, once a day, once everytwo days, three times a week, twice a week, and once a week.

Localized delivery is also contemplated, including but not limited todelivery techniques in which the compound is implanted, injected,infused, or otherwise locally delivered. Localized delivery ischaracterized by higher concentrations of drug at the site of desiredaction (e.g., the tumor or organ to be treated) versus systemicconcentrations of the drug. Well-known localized delivery forms can beused, including long-acting injections; infusion directly into the siteof action; depot delivery forms; controlled or sustained deliverycompositions; transdermal patches; infusion pumps; and the like. The CSAcan further be incorporated into a biodegradable or bioerodible materialor be put into or on a medical device.

Doses may vary depending upon whether the treatment is therapeutic orprophylactic, the onset, progression, severity, frequency, duration,probability of or susceptibility of the symptom, the type pathogenesisto which treatment is directed, clinical endpoint desired, previous,simultaneous or subsequent treatments, general health, age, gender orrace of the subject, bioavailability, potential adverse systemic,regional or local side effects, the presence of other disorders ordiseases in the subject, and other factors that will be appreciated bythe skilled artisan (e.g., medical or familial history). Dose amount,frequency or duration may be increased or reduced, as indicated by theclinical outcome desired, status of the infection, symptom or pathology,any adverse side effects of the treatment or therapy. The skilledartisan will appreciate the factors that may influence the dosage,frequency and timing required to provide an amount sufficient oreffective for providing a prophylactic or therapeutic effect or benefit.The exact dosage will be determined by the practitioner, in light offactors related to the subject that requires treatment. Dosage andadministration are adjusted to provide sufficient levels of the activeagent(s) or to maintain the desired effect. It will be appreciated thattreatment as described herein includes preventing a disease,ameliorating symptoms, slowing disease progression, reversing damage, orcuring a disease.

The dosage may range broadly, depending upon the desired effects and thetherapeutic indication. Alternatively dosages may be based andcalculated upon the surface area of the patient, as understood by thoseof skill in the art. Although the exact dosage will be determined on adrug-by-drug basis, in most cases, some generalizations regarding thedosage can be made. The systemic daily dosage regimen for an adult humanpatient may be, for example, an oral dose of between 0.01 mg and 3000 mgof the active ingredient, preferably between 1 mg and 700 mg, e.g. 5 to200 mg. The dosage may be a single one or a series of two or more givenin the course of one or more days, as is needed by the subject. In someembodiments, the compounds will be administered for a period ofcontinuous therapy, for example for a week or more, or for months oryears. Doses tailored for particular types of cancers or particularpatients can be selected based, in part, on the GI₅₀, TGI, and LC₅₀values set forth in the Examples that follow.

In instances where human dosages for compounds have been established forat least some condition, those same dosages may be used, or dosages thatare between about 0.1% and 500%, more preferably between about 25% and250% of the established human dosage. Where no human dosage isestablished, as will be the case for newly-discovered pharmaceuticalcompositions, a suitable human dosage can be inferred from ED₅₀ or ID₅₀values, or other appropriate values derived from in vitro or in vivostudies, as qualified by toxicity studies and efficacy studies inanimals.

In cases of administration of a pharmaceutically acceptable salt,dosages may be calculated as the free base. As will be understood bythose of skill in the art, in certain situations it may be necessary toadminister the compounds disclosed herein in amounts that exceed, oreven far exceed, the above-stated, preferred dosage range in order toeffectively and aggressively treat particularly aggressive diseases orconditions.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain themodulating effects, or minimal effective concentration (MEC). Forexample, therapeutic dosages may result in plasma levels of 0.05 μg/mL,0.1 μg/mL, 0.5 μg/mL, 1 μg/mL, 5 μg/mL, 10 μg/mL, 15 μg/mL, 20 μg/mL,g/mL, 30 μg/mL, 35 μg/mL, 40 μg/mL, 45 μg/mL, 50 μg/mL, 55 μg/mL, 60μg/mL, 65 g/mL, 70 μg/mL, 75 μg/mL, 80 μg/mL, 85 μg/mL, 90 μg/mL, 95μg/mL, 100 μg/mL, a range bounded by any two of the aforementionednumbers, or about any of the aforementioned numbers and ranges. In someembodiments, the therapeutic dose is sufficient to establish plasmalevels in the range of about 0.1 μg/mL to about 10 μg/mL. In otherembodiments, the therapeutic dose is sufficient to establish plasmalevels in the range of 1 g/mL to 20 μg/mL. The MEC will vary for eachcompound but can be estimated from in vitro data. Dosages necessary toachieve the MEC will depend on individual characteristics and route ofadministration. However, HPLC assays or bioassays can be used todetermine plasma concentrations. Dosage intervals can also be determinedusing MEC value. Compositions should be administered using a regimenwhich maintains plasma levels above the MEC for 10-90% of the time,preferably between 30-90% and most preferably between 50-90%. In casesof local administration or selective uptake, the effective localconcentration of the drug may not be related to plasma concentration.

Compounds disclosed herein can be evaluated for efficacy and toxicityusing known methods. For example, the toxicology of a particularcompound, or of a subset of the compounds, sharing certain chemicalmoieties, may be established by determining in vitro toxicity towards acell line, such as a mammalian, and preferably human, cell line. Theresults of such studies are often predictive of toxicity in animals,such as mammals, or more specifically, humans. Alternatively, thetoxicity of particular compounds in an animal model, such as mice, rats,rabbits, or monkeys, may be determined using known methods. The efficacyof a particular compound may be established using several recognizedmethods, such as in vitro methods, animal models, or human clinicaltrials. When selecting a model to determine efficacy, the skilledartisan can be guided by the state of the art to choose an appropriatemodel, dose, route of administration and/or regime.

As described herein, the methods of the embodiments also include the useof a compound or compounds as described herein together with one or moreadditional therapeutic agents for the treatment of disease conditions.Thus, for example, the combination of active ingredients may be: (1)co-formulated and administered or delivered simultaneously in a combinedformulation; (2) delivered by alternation or in parallel as separateformulations; or (3) by any other combination therapy regimen known inthe art. When delivered in alternation therapy, the methods describedherein may comprise administering or delivering the active ingredientssequentially, e.g., in separate solution, emulsion, suspension, tablets,pills or capsules, or by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas insimultaneous therapy, effective dosages of two or more activeingredients are administered together. Various sequences of intermittentcombination therapy may also be used.

Examples Synthesis of CSAs:

Compounds described herein can be prepared by known methods, such asthose disclosed in U.S. Pat. No. 6,350,738, which are incorporatedherein by reference. A skilled artisan will readily understand thatminor variations of starting materials and reagents may be utilized toprepare known and novel cationic steroid antimicrobials. For example,the preparation of CSA-13 disclosed in U.S. Pat. No. 6,350,738 (compound133) can be used to prepare CSA-92 by using hexadecylamine rather thanoctyl amine as disclosed. Schematically, for example, the preparation ofcertain compounds can be accomplished as follows:

As shown above, compound 1-A is converted to the mesylate, compound 1-Busing known conditions. Treatment of compound 1-B with a secondaryamine, such as HNR₁R₂, results in the formation of compound 1-C, whoseazido functional groups are reduced with hydrogen gas in the presence ofa suitable catalyst to afford compound 1-D. Suitable catalysts includePalladium on Carbon and Lindlar catalyst. The reagent HNR₁R₂ is notparticularly limited under this reaction scheme. For example, when R₁ ishydrogen and R₂ is a C₈-alkyl, CSA-13 is obtained from the synthesis.When R₁ is hydrogen and R₂ is a C₁₆-alkyl, CSA-92 is obtained from thesynthesis. When R₁ and R₂ are both C₅-alkyl, CSA-90 is obtained from thesynthesis.

Anti-Cancer Activity:

The antiproliferative activity of compounds were determined in theNational Cancer Institute (NCI) screen (Drug. Dev. Res. 1995, 34,91-109; J. Natl. Cancer Inst. 1990, 82, 1107-1112; Drug Dev. Res. 1995,34, 91-109). For certain compounds, cells of approximately 60 differenthuman cancer cell lines were incubated for 48 hours with five 10-folddilutions of the tested compounds starting from 100 μM and then treatedwith sulforhodamine B dye. For other compounds, cells of approximately60 different human cancer cell lines were incubated for 48 hours with aconcentration of 10 μM test compound. The ratios of recorded opticaldensities relative to that of the control were plotted as a function ofthe common logarithm of the tested compound concentrations or growthpercent (for single concentration tests). The interpolation between thepoints located above and below the 50% percentage growth provided 50%growth inhibition (GI₅₀) values. Total growth inhibition (TGI) and 50%lethal concentrations (LC₅₀) were also calculated using reportedmethods. A “−” means not tested and/or not-determined.

CSA-13

Panel/Cell Line GI₅₀ μM TGI μM LC₅₀ μM Leukemia K-562 1.04 2.47 — MOLT-41.25 2.93 — RPMI-8226 0.266 0.911 — SR 0.272 2.29 — Non-Small Cell LungCancer A549/ATCC 2.01 9.33 45.9 EKVX 1.32 3.38 8.62 HOP-62 0.806 2.969.74 HOP-92 0.408 21.2 >100 NCI-H226 2.22 12.8 66.8 NCI-H23 1.24 3.127.87 NCI-H322M 1.36 9.31 >100 NCI-H460 1.21 3.92 15.5 NCI-H522 2.5910.5 >100 Colon Cancer COLO 205 1.27 3.02 — HCC-2998 1.51 3.98 13.3HCT-116 0.87 2.61 7.25 HCT-15 2.63 14.8 63.9 HT29 1.11 5.31 34.0 KM120.586 2.76 — SW-620 1.16 2.67 — CNS Cancer SF-268 1.50 3.70 9.14 SF-2950.496 2.66 24.0 SF-539 0.318 1.41 4.89 SNB-19 1.49 5.05 89.3 SNB-75 1.765.93 57.2 U251 1.37 3.05 6.81 Melanoma LOX IMVI 0.378 1.73 — MALME-3M1.76 3.88 — M14 1.18 3.52 12.6 SK-MEL-2 4.51 >100 >100 SK-MEL-28 0.2911.27 5.46 SK-MEL-5 0.504 1.92 — UACC-257 2.71 9.00 97.9 UACC-62 0.4822.29 9.43 Ovarian Cancer IGROV1 1.44 3.54 8.67 OVCAR-3 2.24 14.8 88.0OVCAR-4 5.51 25.2 83.0 OVCAR-5 1.55 9.44 58.4 OVCAR-8 1.64 4.01 9.82SK-OV-3 3.45 16.3 93.1 Renal Cancer 786-0 0.837 2.26 5.40 ACHN 1.48 3.689.17 CAKI-1 2.05 10.6 68.0 RXF 393 1.54 15.6 >100 SN12C 0.571 3.55 27.0TK-10 0.974 4.70 >100 UO-31 1.49 — >100 Prostate Cancer PC-33.74 >100 >100 DU-145 1.14 2.35 4.85 Breast Cancer MCF7 1.63 3.09 5.85NCI-ADR-RES 1.83 5.33 36.5 MDA-MB-231/ATCC 0.422 4.08 >100 HS 578T 0.8542.35 — MDA-MB-435 0.318 1.46 5.68 BT-549 1.07 3.28 >100 T-47D 1.92 7.13>100

CSA-44

Panel/Cell Line Growth Percent Leukemia CCRF-CEM −37.46 HL-60(TB) 43.69K-562 −74.53 MOLT-4 26.15 RPMI-8226 77.75 SR −12.92 Non-Small Cell LungCancer A549/ATCC 81.31 HOP-62 37.66 HOP-92 40.75 NCI-H226 89.76 NCI-H2390.31 NCI-H322M 71.42 NCI-H460 73.70 NCI-H522 10.80 Colon Cancer COLO205 66.35 HCC-2998 84.20 HCT-116 49.30 HCT-15 101.79 HT29 39.62 KM1277.75 SW-620 20.01 CNS Cancer SF-268 69.72 SF-539 56.26 SNB-19 115.74SNB-75 63.88 Melanoma LOX IMVI 63.17 MALME-3M 67.83 M14 84.43 MDA-MB-43574.13 SK-MEL-2 126.21 SK-MEL-28 58.43 SK-MEL-5 96.98 UACC-62 103.61Ovarian Cancer IGROV1 77.22 OVCAR-3 107.53 OVCAR-4 75.66 OVCAR-5 92.12OVCAR-8 69.53 NCl/ADR-RES 100.83 SK-OV-3 90.91 Renal Cancer 786-0 99.05A498 130.78 ACHN 96.19 CAKI-1 107.94 RXF 393 108.72 SN12C 77.59 TK-10135.94 U0-31 104.69 Prostate Cancer PC-3 87.30 DU-145 74.35 BreastCancer MCF7 10.84 MDA-MB-231/ATCC 69.26 HS 578T 79.51 BT-549 124.30T-47D 88.83 MDA-MB-468 3.95

CSA-90

Panel/Cell Line Growth Percent Leukemia CCRF-CEM 15.29 HL-60(TB) −16.84K-562 −19.42 MOLT-4 41.11 RPMI-8226 −17.73 SR 19.21 Non-Small Cell LungCancer A549/ATCC 55.21 HOP-62 48.28 HOP-92 50.03 NCI-H226 75.25 NCI-H2349.16 NCI-H322M 24.61 NCI-H460 45.20 NCI-H522 28.85 Colon Cancer COLO205 52.08 HCC-2998 59.63 HCT-116 22.71 HCT-15 72.31 HT29 24.49 KM1222.46 SW-620 45.90 CNS Cancer SF-268 87.47 SF-539 −21.94 SNB-19 61.03SNB-75 70.61 Melanoma LOX IMVI 3.00 MALME-3M 62.21 M14 42.81 MDA-MB-435−13.61 SK-MEL-28 27.91 SK-MEL-5 25.14 UACC-62 13.55 Ovarian CancerIGROV1 29.55 OVCAR-3 107.13 OVCAR-4 85.16 OVCAR-5 66.15 OVCAR-8 55.32NCI/ADR-RES 76.04 SK-OV-3 93.22 Renal Cancer 786-0 61.11 A498 92.77 ACHN54.72 CAKI-1 75.81 RXF 393 87.11 SN12C 54.27 UO-31 65.22 Prostate CancerPC-3 80.53 DU-145 76.50 Breast Cancer MCF7 74.77 MDA-MB-231/ATCC 36.97HS 578T 66.91 BT-549 54.97 T-47D 68.11 MDA-MB-468 71.06

CSA-92

Panel/Cell Line Growth Percent Leukemia CCRF-CEM −45.52 HL-60(TB) 4.50K-562 −34.68 MOLT-4 −33.70 RPMI-8226 −15.39 SR 2.63 Non-Small Cell LungCancer A549/ATCC −57.98 HOP-62 −49.53 HOP-92 −33.16 NCI-H226 −1.42NCI-H23 −39.72 NCI-H322M −76.83 NCI-H460 −45.47 NCI-H522 −43.60 ColonCancer COLO 205 −40.80 HCC-2998 −32.41 HCT-116 −16.64 HCT-15 7.08 HT29−40.97 KM12 −24.28 SW-620 −25.31 CNS Cancer SF-268 −38.18 SF-539 −68.05SNB-19 −66.56 SNB-75 −64.78 Melanoma LOX IMVI −60.40 MALME-3M −60.74 M14−28.70 MDA-MB-435 −28.31 SK-MEL-28 −64.73 SK-MEL-5 3.14 UACC-62 −64.22Ovarian Cancer IGROV1 −41.76 OVCAR-3 −10.46 OVCAR-4 −37.10 OVCAR-5 −3.67OVCAR-8 −48.90 NCI/ADR-RES −60.60 SK-OV-3 −45.67 Renal Cancer 786-0−43.08 A498 −5.88 ACHN −26.45 CAKI-1 −70.80 RXF 393 −41.21 SN12C −82.86TK-10 −60.33 UO-31 −52.51 Prostate Cancer PC-3 −14.45 DU-145 −82.24Breast Cancer MCF7 −44.27 MDA-MB-231/ATCC −98.22 HS 578T −34.00 BT-549−26.02 T-47D −20.87 MDA-MB-468 −55.21

CONCLUSION

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it will be understood by those of skill in the art thatnumerous and various modifications can be made without departing fromthe spirit of the present disclosure. Therefore, it should be clearlyunderstood that the forms disclosed herein are illustrative only and arenot intended to limit the scope of the present disclosure, but rather toalso cover all modification and alternatives coming with the true scopeand spirit of the invention.

1. A method of therapeutically treating cancer, comprising: identifyinga patient in need of therapeutic treatment of a cancer; andadministering to the patient a therapeutically effective amount of anon-isotopically labeled and radio-stable cationic steroid antimicrobial(CSA) of Formula I, or a pharmaceutically acceptable salt thereof, in anamount so as to therapeutically treat the cancer by killing or reducingproliferation of cancerous cells:

where, rings A, B, C, and D are independently saturated, or are fully orpartially unsaturated, provided that at least two of rings A, B, C, andD are saturated; m, n, p, and q are independently 0 or 1; R₁ through R₄,R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ are independently selected from thegroup consisting of hydrogen, hydroxyl, substituted or unsubstitutedalkyl, substituted or unsubstituted hydroxyalkyl, substituted orunsubstituted alkyloxyalkyl, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkyl,substituted or unsubstituted alkylaminoalkylamino, substituted orunsubstituted alkylaminoalkylaminoalkylamino, substituted orunsubstituted aminoalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylaminoalkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, oxo, linking group attached to a second CSA, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedaminoalkyloxyalkyl, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted aminoalkylcarboxamido, substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,substituted or unsubstituted azidoalkyloxy, substituted or unsubstitutedcyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstitutedguanidinoalkyloxy, substituted or unsubstituted quaternary ammoniumalkylcarboxy, and substituted or unsubstituted guanidinoalkyl carboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted hydroxyalkyl, substituted or unsubstitutedalkyloxyalkyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted aryl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl, oxo,linking group attached to a second CSA, substituted or unsubstitutedaminoalkyloxy, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group, provided that at least two of R₁₋₄, R₆, R₇, R₁₁, R₁₂,R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the groupconsisting of substituted or unsubstituted aminoalkyl, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkylamino,substituted or unsubstituted alkylaminoalkylaminoalkylamino, substitutedor unsubstituted aminoalkylcarboxy, substituted or unsubstitutedarylaminoalkyl, substituted or unsubstitutedaminoalkyloxyaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylcarboxyamido, quaternary ammonium alkylcarboxy, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstituted guanidinoalkyloxy,and substituted or unsubstituted guanidinoalkylcarboxy.
 2. The method ofclaim 1, wherein R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ areindependently selected from the group consisting of hydrogen, hydroxyl,substituted or unsubstituted (C₁-C₁₈) alkyl, substituted orunsubstituted (C₁-C₁₈) hydroxyalkyl, substituted or unsubstituted(C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)alkylcarboxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈)alkyl, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, substituted or unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, substituted orunsubstituted (C₁-C₁₈) aminoalkyl, substituted or unsubstituted aryl,substituted or unsubstituted arylamino-(C₁-C₁₈) alkyl, substituted orunsubstituted (C₁-C₁₈) haloalkyl, substituted or unsubstituted C₂-C₆alkenyl, substituted or unsubstituted C₂-C₆ alkynyl, oxo, linking groupattached to a second CSA, substituted or unsubstituted (C₁-C₁₈)aminoalkyloxy, substituted or unsubstituted (C₁-C₁₈)aminoalkyloxy-(C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxy, substituted or unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, substituted or unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, substitutedor unsubstituted (C₁-C₁₈) azidoalkyloxy, substituted or unsubstituted(C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted orunsubstituted (C₁-C₁₈) guanidinoalkyloxy, substituted or unsubstituted(C₁-C₁₈) quaternary ammonium alkylcarboxy, and substituted orunsubstituted (C₁-C₁₈) guanidinoalkyl carboxy, where Q₅ is a side chainof an amino acid, and P.G. is an amino protecting group; R₅, R₈, R₉,R₁₀, R₁₃, R₁₄ and R₁₇ are independently deleted when one of rings A, B,C, or D is unsaturated so as to complete the valency of the carbon atomat that site, or R₅, R₈, R₉, R₁₀, R₁₃, and R₁₄ are independentlyselected from the group consisting of hydrogen, hydroxyl, substituted orunsubstituted (C₁-C₁₈) alkyl, substituted or unsubstituted (C₁-C₁₈)hydroxyalkyl, substituted or unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈)alkyl, substituted or unsubstituted (C₁-C₁₈) aminoalkyl, substituted orunsubstituted aryl, substituted or unsubstituted (C₁-C₁₈) haloalkyl,substituted or unsubstituted (C₂-C₆) alkenyl, substituted orunsubstituted (C₂-C₆) alkynyl, oxo, a linking group attached to a secondCSA, substituted or unsubstituted (C₁-C₁₈) aminoalkyloxy, substituted orunsubstituted (C₁-C₁₈) aminoalkylcarboxy, substituted or unsubstituted(C₁-C₁₈) aminoalkylaminocarbonyl, substituted or unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, substitutedor unsubstituted (C₁-C₁₈) azidoalkyloxy, substituted or unsubstituted(C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted orunsubstituted (C₁-C₁₈) guanidinoalkyloxy, and (C₁-C₁₈)guanidinoalkylcarboxy, where Q₅ is a side chain of an amino acid, andP.G. is an amino protecting group; provided that at least two of R₁₋₄,R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected fromthe group consisting of substituted or unsubstituted (C₁-C₁₈)aminoalkyl, substituted or unsubstituted (C₁-C₁₈) aminoalkyloxy,substituted or unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈) alkyl,substituted or unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino,substituted or unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino(C₁-C₁₈) alkylamino, substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxy, substituted or unsubstituted arylamino (C₁-C₁₈)alkyl, substituted or unsubstituted (C₁-C₁₈) aminoalkyloxy (C₁-C₁₈)aminoalkylaminocarbonyl, substituted or unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, substituted or unsubstituted (C₁-C₁₈)aminoalkylcarboxyamido, a substituted or unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, substituted or unsubstituted di(C₁-C₁₈alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—, substitutedor unsubstituted (C₁-C₁₈) azidoalkyloxy, substituted or unsubstituted(C₁-C₁₈) cyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted orunsubstituted (C₁-C₁₈) guanidinoalkyloxy, and substituted orunsubstituted (C₁-C₁₈) guanidinoalkylcarboxy.
 3. The method of claim 2,wherein R₁ through R₄, R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ areindependently selected from the group consisting of hydrogen, hydroxyl,an unsubstituted (C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) hydroxyalkyl,unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)alkylcarboxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkylamino, (C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino,an unsubstituted (C₁-C₁₈) aminoalkyl, an unsubstituted aryl, anunsubstituted arylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈)aminoalkyloxy, an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl,an unsubstituted (C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; provided that at least two of R₁₋₄, R₆, R₇, R₁₁,R₁₂, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the groupconsisting of hydrogen, hydroxyl, an unsubstituted (C₁-C₁₈) alkyl,unsubstituted (C₁-C₁₈) hydroxyalkyl, unsubstituted (C₁-C₁₈)alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) alkylcarboxy-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkyl, unsubstituted(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted(C₁-C₁₈) aminoalkyl, an unsubstituted aryl, an unsubstitutedarylamino-(C₁-C₁₈) alkyl, oxo, an unsubstituted (C₁-C₁₈) aminoalkyloxy,an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl, an unsubstituted(C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy.
 4. The method of claim 3, wherein thenon-isotopically labeled and radio-stable CSA, or a pharmaceuticallyacceptable salt thereof, is selected from the compound of Formula (II):


5. The method of claim 4, wherein rings A, B, C, and D are independentlysaturated.
 6. The method of claim 5, wherein R₃, R₇, R₁₂, and R₁₈ areindependently selected from the group consisting of hydrogen, anunsubstituted (C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈) hydroxyalkyl,unsubstituted (C₁-C₁₈) alkyloxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)alkylcarboxy-(C₁-C₁₈) alkyl, unsubstituted (C₁-C₁₈)alkylamino-(C₁-C₁₈)alkyl, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkylamino, unsubstituted (C₁-C₁₈) alkylamino-(C₁-C₁₈)alkylamino-(C₁-C₁₈) alkylamino, an unsubstituted (C₁-C₁₈) aminoalkyl, anunsubstituted arylamino-(C₁-C₁₈) alkyl, an unsubstituted (C₁-C₁₈)aminoalkyloxy, an unsubstituted (C₁-C₁₈) aminoalkyloxy-(C₁-C₁₈) alkyl,an unsubstituted (C₁-C₁₈) aminoalkylcarboxy, an unsubstituted (C₁-C₁₈)aminoalkylaminocarbonyl, an unsubstituted (C₁-C₁₈)aminoalkylcarboxamido, an unsubstituted di(C₁-C₁₈ alkyl)aminoalkyl,unsubstituted (C₁-C₁₈) guanidinoalkyloxy, unsubstituted (C₁-C₁₈)quaternary ammonium alkylcarboxy, and unsubstituted (C₁-C₁₈)guanidinoalkyl carboxy; and R₁, R₂, R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₁, R₁₃,R₁₄, R₁₅, R₁₆, and R₁₇ are independently selected from the groupconsisting of hydrogen and unsubstituted (C₁-C₆) alkyl.
 7. The method ofclaim 6, wherein R₃, R₇, R₁₂, and R₁₈ are independently selected fromthe group consisting of hydrogen, an unsubstituted (C₁-C₆) alkyl,unsubstituted (C₁-C₆) hydroxyalkyl, unsubstituted (C₁-C₁₆)alkyloxy-(C₁-C₅) alkyl, unsubstituted (C₁-C₁₆) alkylcarboxy-(C₁-C₅)alkyl, unsubstituted (C₁-C₁₆) alkylamino-(C₁-C₅)alkyl, (C₁-C₁₆)alkylamino-(C₁-C₅) alkylamino, unsubstituted (C₁-C₁₆)alkylamino-(C₁-C₁₆) alkylamino-(C₁-C₅) alkylamino, an unsubstituted(C₁-C₁₆) aminoalkyl, an unsubstituted arylamino-(C₁-C₅) alkyl, anunsubstituted (C₁-C₅) aminoalkyloxy, an unsubstituted (C₁-C₁₆)aminoalkyloxy-(C₁-C₅) alkyl, an unsubstituted (C₁-C₅) aminoalkylcarboxy,an unsubstituted (C₁-C₅) aminoalkylaminocarbonyl, an unsubstituted(C₁-C₅) aminoalkylcarboxamido, an unsubstituted di(C₁-C₅alkyl)amino-(C₁-C₅) alkyl, unsubstituted (C₁-C₅) guanidinoalkyloxy,unsubstituted (C₁-C₁₆) quaternary ammonium alkylcarboxy, andunsubstituted (C₁-C₁₆) guanidinoalkylcarboxy.
 8. The method of claim 7,wherein R₁, R₂, R₄, R₅, R₆, R₈, R₁₀, R₁₁, R₁₄, R₁₆, and R₁₇ are eachhydrogen; and R₉ and R₁₃ are each methyl.
 9. The method of claim 8,wherein R₃, R₇, and R₁₂ are independently selected from the groupconsisting of aminoalkyloxy and aminoalkylcarboxy; and R₁₈ is selectedfrom the group consisting of alkylaminoalkyl; alkoxycarbonylalkyl;alkylcarbonyloxyalkyl; di(alkyl)aminoalkyl; alkylaminoalkyl;alkyoxycarbonylalkyl; and alkylcarboxyalkyl.
 10. The method of claim 1,wherein R₃, R₇, R₁₂, and R₁₈ are independently selected from the groupconsisting of amino-C₃-alkyloxy; amino-C₃-alkyl-carboxy;C₈-alkylamino-C₅-alkyl; C₈-alkoxy-carbonyl-C₄-alkyl;C₁₀-alkoxy-carbonyl-C₄-alkyl; C₈-alkyl-carbonyl-C₄-alkyl;di-(C₅-alkyl)amino-C₅-alkyl; C₁₃-alkylamino-C₅-alkyl;C₆-alkoxy-carbonyl-C₄-alkyl; C₆-alkyl-carboxy-C₄-alkyl; andC₁₆-alkylamino-C₅-alkyl.
 11. The method of claim 1, wherein the canceris a non-viral induced cancer.
 12. The method of claim 1, wherein thecancer is a cancer of the gastrointestinal tract.
 13. The method ofclaim 12, wherein the cancer of the gastrointestinal tract is selectedfrom rectal cancer, colon cancer, and pancreatic cancer.
 14. The methodof claim 1, wherein the cancer is a bone cancer.
 15. The method of claim14, wherein the bone cancer is selected from multiple myeloma, sarcoma,and leukemia.
 16. A method of therapeutically treating cancer,comprising: identifying a patient in need of therapeutic treatment of acancer selected from gastrointestinal tract cancer and bone cancer; andadministering to the patient a therapeutically effective amount of anon-isotopically labeled and radio-stable cationic steroid antimicrobial(CSA) of Formula I, or a pharmaceutically acceptable salt thereof, in anamount so as to therapeutically treat the cancer by killing or reducingproliferation of cancerous cells:

where, rings A, B, C, and D are independently saturated, or are fully orpartially unsaturated, provided that at least two of rings A, B, C, andD are saturated; m, n, p, and q are independently 0 or 1; R₁ through R₄,R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ are independently selected from thegroup consisting of hydrogen, hydroxyl, substituted or unsubstitutedalkyl, substituted or unsubstituted hydroxyalkyl, substituted orunsubstituted alkyloxyalkyl, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkyl,substituted or unsubstituted alkylaminoalkylamino, substituted orunsubstituted alkylaminoalkylakylaminoalkylamino, substituted orunsubstituted aminoalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylaminoalkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, oxo, linking group attached to a second CSA, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedaminoalkyloxyalkyl, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted aminoalkylcarboxamido, substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,substituted or unsubstituted azidoalkyloxy, substituted or unsubstitutedcyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstitutedguanidinoalkyloxy, substituted or unsubstituted quaternary ammoniumalkylcarboxy, and substituted or unsubstituted guanidinoalkyl carboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted hydroxyalkyl, substituted or unsubstitutedalkyloxyalkyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted aryl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl, oxo,linking group attached to a second CSA, substituted or unsubstitutedaminoalkyloxy, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group, provided that at least two of R₁₋₄, R₆, R₇, R₁₁, R₁₂,R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the groupconsisting of substituted or unsubstituted aminoalkyl, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkylamino,substituted or unsubstituted alkylaminoalkylaminoalkylamino, substitutedor unsubstituted aminoalkylcarboxy, substituted or unsubstitutedarylaminoalkyl, substituted or unsubstitutedaminoalkyloxyaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylcarboxyamido, quaternary ammonium alkylcarboxy, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstituted guanidinoalkyloxy,and substituted or unsubstituted guanidinoalkylcarboxy.
 17. A method oftherapeutically or prophylactically treating cancer, comprising:identifying a patient in need of therapeutic or prophylactic treatmentof a non-viral induced cancer; and administering to the patient atherapeutically effective amount of a non-isotopically labeled andradio-stable cationic steroid antimicrobial (CSA) of Formula I, or apharmaceutically acceptable salt thereof, in an amount so as totherapeutically treat the non-viral induced cancer by killing orreducing proliferation of cancerous cells:

where, rings A, B, C, and D are independently saturated, or are fully orpartially unsaturated, provided that at least two of rings A, B, C, andD are saturated; m, n, p, and q are independently 0 or 1; R₁ through R₄,R₆, R₇, R₁₁, R₁₂, R₁₅, R₁₆, and R₁₈ are independently selected from thegroup consisting of hydrogen, hydroxyl, substituted or unsubstitutedalkyl, substituted or unsubstituted hydroxyalkyl, substituted orunsubstituted alkyloxyalkyl, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkyl,substituted or unsubstituted alkylaminoalkylamino, substituted orunsubstituted alkylaminoalkylaminoalkylamino, substituted orunsubstituted aminoalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted arylaminoalkyl, substituted or unsubstituted haloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, oxo, linking group attached to a second CSA, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedaminoalkyloxyalkyl, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted aminoalkylcarboxamido, substituted or unsubstituteddi(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—, H₂N—HC(Q₅)-C(O)—N(H)—,substituted or unsubstituted azidoalkyloxy, substituted or unsubstitutedcyanoalkyloxy, P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstitutedguanidinoalkyloxy, substituted or unsubstituted quaternary ammoniumalkylcarboxy, and substituted or unsubstituted guanidinoalkyl carboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group; and R₅, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₇ areindependently deleted when one of rings A, B, C, or D is unsaturated soas to complete the valency of the carbon atom at that site, or R₅, R₈,R₉, R₁₀, R₁₃, and R₁₄ are independently selected from the groupconsisting of hydrogen, hydroxyl, substituted or unsubstituted alkyl,substituted or unsubstituted hydroxyalkyl, substituted or unsubstitutedalkyloxyalkyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted aryl, substituted or unsubstituted haloalkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl, oxo,linking group attached to a second CSA, substituted or unsubstitutedaminoalkyloxy, substituted or unsubstituted aminoalkylcarboxy,substituted or unsubstituted aminoalkylaminocarbonyl, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, guanidinoalkyloxy, and guanidinoalkylcarboxy,where Q₅ is a side chain of an amino acid, and P.G. is an aminoprotecting group, provided that at least two of R₁₋₄, R₆, R₇, R₁₁, R₁₂,R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the groupconsisting of substituted or unsubstituted aminoalkyl, substituted orunsubstituted aminoalkyloxy, substituted or unsubstitutedalkylcarboxyalkyl, substituted or unsubstituted alkylaminoalkylamino,substituted or unsubstituted alkylaminoalkylaminoalkylamino, substitutedor unsubstituted aminoalkylcarboxy, substituted or unsubstitutedarylaminoalkyl, substituted or unsubstitutedaminoalkyloxyaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylaminocarbonyl, substituted or unsubstitutedaminoalkylcarboxyamido, quaternary ammonium alkylcarboxy, substituted orunsubstituted di(alkyl)aminoalkyl, H₂N—HC(Q₅)-C(O)—O—,H₂N—HC(Q₅)-C(O)—N(H)—, azidoalkyloxy, cyanoalkyloxy,P.G.-HN—HC(Q₅)-C(O)—O—, substituted or unsubstituted guanidinoalkyloxy,and substituted or unsubstituted guanidinoalkylcarboxy.
 18. The methodof claim 17, wherein the non-viral induced cancer is a carcinoma. 19.The method of claim 17, wherein the non-viral induced cancer is asarcoma.
 20. The method of claim 17, wherein the non-viral inducedcancer is a lymphoma or a myeloma.